Azolo triazines and pyrimidines

ABSTRACT

Corticotropin releasing factor (CRF) antagonists of formula I or II: ##STR1## and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivityassociated with psychopathological disturbance andstress.

This application claims the benefit of U.S. Provisional ApplicationSer. No. 60/023,290, filed Jul. 24, 1996.

FIELD OF THE INVENTION

This invention relates a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivityassociated with psychopathological disturbance andstress, by administration of certain [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC) -derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapoisky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have beendemonstrated in a variety of behavioral anxietymodels [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050 , Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.

Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses.

For instance, EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazine compounds of the formula ##STR2## where R¹ is OH or alkanoyl, R² is H, OH, or SH, and R³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout.

EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula ##STR3## where A is CH or N, R⁰ and R³ are H or alkyl, and R¹ and R² are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma.

U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula: ##STR4## where R¹ is CH₃, C₂ H₅ or C₆ H₅, X is H, C₆ H₅, m--CH₃ C₆ H₄, CN, COOEt, Cl, I or Br, Y is H, C₆ H₅, o--CH₃ C₆ H₄, or p--CH₃ C₆ H₄, and Z is OH, H, CH₃, C₂ H₅, C₆ H₅, n--C₃ H₇, i--C₃ H₇, SH, SCH₃, NHC₄ H₉, or N(C₂ H₅)₂, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula: ##STR5## where R¹ is H or alkyl, R² is H or alkyl, R³ is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators.

U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula ##STR6## where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout.

U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula ##STR7## where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R₆ -R₈ are H, alkyl, etc., and R₉ is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants.

U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula ##STR8## where A can be N, B can be CR₃, R₃ can be phenyl or substituted phenyl, etc., R is --N(R₄)SO₂ R₅ or --SO₂ N (R₆) R₇ and R₁ and R₂ can be taken together to form ##STR9## where X, Y and Z are H, alkyl, acyl, etc. and D is O or S.

U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines cAMP phosphodiesterase inhibitors of the formula ##STR10## where Z is H, OH, CH₃, C₂ H₅, C₆ H₅, n--C₃ H₇, iso--C₃ H₇, SH, SCH₃, NH(n--C₄ H₉), or N (C₂ H₅)₂, R is H or CH₃, and R₁ is CH₃ or C₂ H₅. The reference lists eight therapeutic areas where inhibitors of CAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula ##STR11## where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R¹ is H, alkyl, etc., R² is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R³ is H, alkyl or phenyl, R⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R⁵ and R⁶ are H or alkyl.

EP 0 591 528 (Otsuka,1991) discloses anti-inflammatory use of pyrazolopyrimidines represented bythe formula ##STR12## where R₁, R₂, R₃ and R₄ are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R₅ is SR₆ or NR₇ R₈, R₆ is pyridyl or optionally substituted phenyl, and R₇ and R₈ are H or optionally substituted phenyl.

Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Pat. Nos. 4021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula ##STR13## where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula ##STR14## where R¹ is CF₃, C₂ F₅, or C₆ H₄ F, and R² is CH₃, C₂ H₅, CF₃, or C₆ H₄ F.

Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-a]pyrimidine of the formula ##STR15##

Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula ##STR16## where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN, 1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem., 22, 601 (1985).

SUMMARY OF THE INVENTION

In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.

The present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.

According to another aspect, the present invention provides novel compounds of Formulae (1) and (2) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formulae (1) and (2), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.

According to yet another aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION

[1] The present invention comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1) or (2): ##STR17## and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein:

A is N or CR;

Z is N or CR² ;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R⁴ groups and each Ar is attached to an unsaturated carbon atom;

R is independently selected at each occurrence from H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₇ cycloalkylalkyl, halo, CN, C₁ -C₄ haloalkyl;

R¹ is independently selected at each occurrence from H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, halo, CN, C₁ -C₄ haloalkyl, C₁ -C₁₂ hydroxyalkyl, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₀ cyanoalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl, NR⁹ R¹⁰, C₁ -C₄ alkyl-NR⁹ R¹⁰, NR⁹ COR¹⁰, OR¹¹, SH or S(O)_(n) R¹² ;

R² is selected from H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl, C₁ -C₄ hydroxyalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, --NR⁶ S(O)_(n) R⁷, S(O)_(n) NR⁶ R⁷, C₁ -C₄ haloalkyl, --OR⁷, SH or --S(O)_(n) R¹² ;

R³ is selected from:

H, OR⁷, SH, S(O)_(n) R¹³, COR⁷, CO₂ R⁷, OC(O)R¹³, NR⁸ COR⁷, N(COR⁷)₂, NR⁸ CONR⁶ R⁷, NR⁸ CO₂ R¹³, NR⁶ R⁷, NR^(6a) R^(7a) N(OR⁷)R⁶, CONR⁶ R⁷, aryl, heteroaryl and heterocyclyl, or

C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₅ -C₈ cycloalkenyl, C₄ C₁₂ cycloalkylalkyl or C₆ -C₁₀ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from: C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, NO₂, halo, CN, C₁ -C₄ haloalkyl, NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, COR⁷, OR⁷, CONR⁶ R⁷, CO(NOR⁹)R⁷, CO₂ R⁷, or S(O)_(n) R⁷, where each such C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, NO₂, halo, CN, NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, COR⁷ OR⁷, CONR⁶ R⁷, CO₂ R⁷, CO(NOR⁹)R⁷, or S(O)_(n) R⁷ ;

R⁶ and R⁷, R^(6a) and R^(7a) are independently selected at each occurrence from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl);

alternatively, NR⁶ R⁷ and NR^(6a) R^(7a) are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C₁ -C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl;

R¹ l is selected from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl;

R¹³ is selected from C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-;

R¹⁴ is selected from C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, or C₄ -C₁₂ cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, and C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl and C₁ -C₆ alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₆ alkyl, C₃ -C₁₀ cycloalkyl, C₄ -C₁₆ cycloalkylalkyl, except that for S(O)_(n) R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵, NR¹⁶ R⁵, and CONR¹⁶ R¹⁵ ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, --COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵,NR⁸ CO₂ R¹⁵, NR¹⁶ R¹⁵, and CONR¹⁶ R¹⁵ ;

heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵, NR¹⁵ R¹⁶, and CONR¹⁶ R¹⁵ ;

n is independently at each occurrence 0, 1 or 2,

[2] Preferred methods of the present invention are methods in wherein in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴ substituents.

[3] Further preferred methods of the above invention are methods wherein, in the compound of Formulae (1) or (2), A is N, Z is CR², Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² are CH₃, and R³ is NR^(6a) R^(7a).

[4] The present invention comprises compounds of Formulae (1) or (2): ##STR18## and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein:

A is N or CR;

Z is N or CR² ;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R⁴ groups and each Ar is attached to an unsaturated carbon atom;

R is independently selected at each occurrence from H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₇ cycloalkylalkyl, halo, CN, C₁ -C₄ haloalkyl;

R¹ is independently selected at each occurrence from H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, halo, CN, C₁ -C₄ haloalkyl, C₁ -C₁₂ hydroxyalkyl, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₀ cyanoalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl, NR⁹ R¹⁰, C₁ -C₄ alkyl--NR⁹ R¹⁰, NR⁹ COR¹⁰, OR¹¹, SH or S(O)_(n) R¹² ;

R² is selected from H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl, C₁ -C₄ hydroxyalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, --NR⁶ S(O)_(n) R⁷, S(O)_(n) NR⁶ R⁷, C₁ -C₄ haloalkyl, --OR⁷, SH or --S(O)_(n) R¹² ;

R³ is selected from:

H, OR⁷, SH, S(O)_(n) R¹³, COR⁷, CO₂ R⁷, OC(O)R¹³, NR⁸ COR⁷, N(COR⁷)₂, NR⁸ CONR⁶ R⁷, NR⁸ CO₂ R¹³, NR⁶ R⁷, NR^(6a) R^(7a), N(OR⁷)R⁶, CONR⁶ R⁷, aryl, heteroaryl and heterocyclyl, or

C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₅ -C₈ cycloalkenyl, C₄ -C₁₂ cycloalkylalkyl or C₆ -C₁₀ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵,aryl, heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from:

C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, NO₂, halo, CN, C₁ -C₄ haloalkyl, NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, COR⁷, OR⁷, CONR⁶ R⁷, CO(NOR⁹)R⁷, CO₂ R⁷, or S(O)_(n) R⁷, where each such C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, NO₂, halo, CN, NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, COR⁷ OR⁷, CONR⁶ R⁷, CO₂ R⁷, CO(NOR⁹)R⁷, or S(O)_(n) R⁷ ;

R⁶ and R⁷, R^(6a) and R^(7a) are independently selected at each occurrence from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl),

alternatively, NR⁶ R⁷ and NR^(6a) R^(7a) are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C₁ -C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl;

R¹¹ is selected from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl;

R¹³ is selected from C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-;

R¹⁴ is selected from C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, or C₄ -C₁₂ cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,and C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl and C₁ -C₆ alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₆ alkyl, C₃ -C₁₀ cycloalkyl, C₄ -C₁₆ cycloalkylalkyl, except that for S(O)_(n) R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵,COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵, NR¹⁶ R¹⁵, and CONR¹⁶ R¹⁵ ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, --COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵,NR¹⁶ R¹⁵, and CONR¹⁶ R¹⁵ ;

heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹⁵, COR¹⁵, CO₂ R¹⁵, OC(O)R¹⁵, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹⁵, NR¹⁵ R¹⁶, and CONR¹⁶ R¹⁵ ;

n is independently at each occurrence 0, 1 or 2,

with the provisos that:

(1) when A is N, Z is CR², R² is H, R³ is --OR⁷ or --OCOR¹³, and R⁷ is H, then R¹ is not H, OH or SH;

(2) when A is N, Z is CR², R¹ is CH₃ or C₂ H₅, R² is H, and R³ is OH, H, CH₃, C₂ H₅, C₆ H₅, n--C₃ H₇, i--C₃ H₇, SH, SCH₃, NHC₄ H₉, or N(C₂ H₅)₂, then Ar is not phenyl or m--CH₃ -phenyl;

(3) when A is N, Z is CR², R² is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R³ is NR^(6a) R^(7a), then R^(6a) and R^(7a) are not H or alkyl;

(4) when A is N, Z is CR², and R² is SO₂ NR⁶ R⁷, then R³ is not OH or SH;

(5) when A is CR and Z is CR², then R² is not --NR⁶ SO₂ R⁷ or --SO₂ NR⁶ R⁷ ;

(6) when A is N, Z is CR² and R² is --NR⁶ SO₂ R⁷ or --SO₂ NR⁶ R⁷, then R³ is not OH or SH;

(7) when A is N, Z is CR², R¹ is methyl or ethyl, R² is H, and R³ is H, OH, CH₃, C₂ H₅, C₆ H₅, n--C₃ H₇, iso--C₃ H₇, SH, SCH₃, NH(n--C₄ H₉), or N(C₂ H₅)₂, then Ar is not unsubstituted phenyl or m-methylphenyl;

(8) when A is CR, Z is CR², R² is H, phenyl or alkyl, R³ is NR⁸ COR⁷ and Ar is phenyl or phenyl substituted with phenylthio, then R⁷ is not aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocycly(C₁ -C₄ alkyl);

(9) when A is CR, Z is CR², R² is H or alkyl, Ar is phenyl, and R³ is SR¹³ or NR^(6a) R^(7a), then R¹³ is not aryl or heteroaryl and R^(6a) and R^(7a) are not H or aryl; or

(10) when A is CH, Z is CR², R¹ is OR¹¹, R² is H, R³ is OR⁷, and R⁷ and R¹¹ are both H, then Ar is not phenyl, p--Br-phenyl, p--Cl-phenyl, p--NHCOCH₃ -phenyl, p--CH₃ -phenyl, pyridyl or naphthyl;

(11) when A is CH, Z is CR², R² is H, Ar is unsubstituted phenyl, and R³ is CH₃, C₂ H₅, CF₃ or C₆ H₄ F, then R₁ is not CF₃ or C₂ F₅ ;

(12) when A is CR, R is H, Z is CR², R² is OH, and R¹ and R³ are H, then Ar is not phenyl;

(13) when A is CR, R is H, Z is CR², R² is OH or NH₂, R¹ and R³ are CH₃, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl.

[5] Preferred compounds of the above invention are compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof with the additional provisos that: (1) when A is N, R¹ is H, C₁ -C₄ alkyl, halo, CN, C₁ -C₁₂ hydroxyalkyl, C₁ -C₄ alkoxyalkyl or SO₂ (C₁ -C₄ alkyl), R³ is NR^(6a) R^(7a) and R^(6a) is unsubstituted C₁ -C₄ alkyl, then R^(7a) is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C₃ -C₆ cycloalkyl; and (2) A is N, R¹ is H, C₁ -C₄ alkyl, halo, CN, C₁ -C₁₂ hydroxyalkyl, C₁ -C₄ alkoxyalkyl or SO₂ (C₁ -C₄ alkyl), R³ is NR^(6a) R^(7a) and R^(7a) is unsubstituted C₁ -C₄ alkyl, then R^(6a) is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C₃ -C₆ cycloalkyl.

[6] Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴ substituents.

[7]. Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N, Z is CR², Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² are CH₃, and R³ is NR^(6a) R^(7a).

[11] More preferred compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N.

[12] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

[13] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

[14] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a) R^(7a) or OR⁷.

[15] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a) R^(7a) or OR⁷.

[16] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR².

[17] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

[18] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a) R^(7a) or OR⁷.

[19] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) is independently selected from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl, heteroaryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-; and

R^(7a) is independently selected at each occurrence from:

H,

C₅ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl);

alternatively, NR⁶ R⁷ and NR^(6a) R^(7a) are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C₁ -C₄ alkyl groups.

[20] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are selected from:

C₁ -C₄ alkyl or C₃ -C₆ cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³,--COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵,NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[21] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) is selected from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl);

R^(7a) is selected from:

C₁ -C₄ alkyl and each such C₁ -C₄ alkyl is substituted with 1-3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl.

[22] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R^(6a) and R^(7a) is selected from:

C₃ -C₆ cycloalkyl, each such C₃ -C₆ cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵,NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁ -C₄ alkyl.

[23] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁ -C₁₀ alkyl, each such C₁ -C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, R⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl.

[24] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a) R^(7a) or OR⁷.

[25] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R⁶ a is independently selected from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl);

R^(7a) is independently selected at each occurrence from:

H,

C₅ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ C₂ R¹³ NR¹⁶ R¹⁵, CONR⁶ R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl),

alternatively, NR⁶ R⁷ and NR^(6a) R^(7a) are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C₁ -C₄ alkyl groups.

[26] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are selected from:

C₁ -C₄ alkyl or C₃ -C₆ cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, --COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[27] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are

C₁ -C₄ alkyl, each such C₁ -C₄ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, --COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵,NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl.

[28] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R⁶ a is selected from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)

R^(7a) is:

C₁ -C₄ alkyl and each such C₁ -C₄ alkyl is substituted with 1-3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵ aryl, heteroaryl or heterocyclyl.

[29] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R^(6a) and R^(7a) is selected from:

C₃ -C₆ cycloalkyl, each such C₃ -C₆ cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁ -C₄ alkyl.

[30] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁ -C₁₀ alkyl, each such C₁ -C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, R⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl.

[31] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents,

R³ is NR^(6a) R^(7a) or OR⁷ and

R¹ and R² are independently selected from H, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl.

[32] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) is independently selected from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl);

R^(7a) is independently selected at each occurrence from:

H,

C₅ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl),

alternatively, NR⁶ R⁷ and NR^(6a) R^(7a) are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C₁ -C₄ alkyl groups.

[33] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are selected from:

C₁ -C₄ alkyl or C₃ -C₆ cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, --COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[34] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are

C₁ -C₄ alkyl, each such C₁ -C₄ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, --COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl.

[35] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) is selected from:

H,

C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₁ -C₁₀ haloalkyl with 1-10 halogens, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₅ -C₁₀ cycloalkenyl, or C₆ -C₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl, aryl(C₁ -C₄ alkyl), heteroaryl, heteroaryl(C₁ -C₄ alkyl), heterocyclyl or heterocyclyl(C₁ -C₄ alkyl);

R⁷ a is:

C₁ -C₄ alkyl and each such C₁ -C₄ alkyl is substituted with 1-3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl.

[36] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R^(6a) and R^(7a) is selected from:

C₃ -C₆ cycloalkyl, each such C₃ -C₆ cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, NR⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵,CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁ -C₄ alkyl.

[37] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁ -C₁₀ alkyl, each such C₁ -C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, R⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵,aryl, heteroaryl or heterocyclyl.

[38] Specifically preferred compounds of the above invention are compounds of Formula (50) ##STR19## and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, selected from the group consisting of:

a compound of Formula (50) wherein R³ is --NHCH(n--Pr)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)(n--Bu), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --(n--Pr)(CH₂ cPr), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(n-Bu), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OEt)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Me)(Ph), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(n--Pr)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(n--Pr), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) Me;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --OEt, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CN)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Me)(CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --OCH(Et)(CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(n--Pr)(CH₂ cPr), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Me)(CH₂ N(Me)₂), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(cPr) (CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(n--Pr)(CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(n--Bu)(CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(CH₂ OMe), R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OEt)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ CH₂ OMe)(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is morpholino, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NH(c--Pr), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is CN, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is --NCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R3 is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is (S)--NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NH(CH₂ OMe)(CH₂ --iPr), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is H, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe) (n--Pr), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OEt)(Et), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is (S)--NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is (S)--NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)(CH₂ CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NH(Et)(CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)(CH₂ CH₂ OH), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ c--Pr) (n--Pr), R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(c--Pr) (CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH (Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(Et)(CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is CN, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is --NHCH(CH₂ OH)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; and

a compound of Formula (50) wherein R³ is N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.

[39] More specifically preferred is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

[40] More specifically preferred is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

[41] More preferred are compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is CR.

[42] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

[43] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

[44] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a) R^(7a) or OR⁷.

[45] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a) R^(7a) or OR⁷.

[46] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR².

[47] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

[48] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a) R^(7a) or OR⁷.

[49] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a) R^(7a) or OR⁷.

[50] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁ -C₁₀ alkyl, and each such C₁ -C₁₀ alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, R⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl.

[51] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents,

R³ is NR^(6a) R^(7a) or OR⁷ and

R¹ and R² are independently selected from H, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl.

[52] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁ -C₁₀ alkyl, and each such C₁ -C₁₀ alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n) R¹³, COR¹⁵, CO₂ R¹⁵, OC(O)R¹³, NR⁸ COR¹⁵, N(COR¹⁵)₂, R⁸ CONR¹⁶ R¹⁵, NR⁸ CO₂ R¹³, NR¹⁶ R¹⁵, CONR¹⁶ R¹⁵, aryl, heteroaryl or heterocyclyl.

[53] Specifically preferred compounds of the above invention are compounds of Formula (51) ##STR20## and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof selected from the group consisting of:

a compound of Formula (51) wherein R³ is --NHCH(n--Pr)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(n--Pr) (CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(n--Bu)(CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(n--Pr)(CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is (S) --NH(CH₂ CH₂ OMe)CH₂ OMe, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NH(CH₂ CH₂ OMe)CH₂ OMe, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NH(Et), R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(n--Pr)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is (S) --NH(CH₂ CH₂ OMe)CH₂ OMe, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NH(CH₂ CH₂ OMe)CH₂ OMe, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(n--Pr) (CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is (S) --NH(CH₂ CH₂ OMe)CH₂ OMe, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NH(CH₂ CH₂ OMe)CH₂ OMe, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(c--Pr) (CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(c--Pr)(CH₂ CH₂ CN), R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH (n--Pr)(CH₂ OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH (n--Pr)(CH₂ OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R⁴ e is H;

a compound of Formula (51) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Pr)(CH₂ CH₂ CN), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --N(Bu)(Et), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)CH₂ OMe, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NHCH(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is --NEt₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; and

a compound of Formula (51) wherein R³ is --N(Pr) (CH₂ CH₂ CN), R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.

[54] More specifically preferred is 7-(3-pentylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

[55] More specifically preferred is 7-(Diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

[56] More specifically preferred is 7-(N-(3-cyanopropyl)--N-propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

The present invention also provides pharmaceutical compositions comprising compounds of Formulae (1) and (2) and a pharmaceutically acceptable carrier.

Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The term "alkyl" includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix "n" means a straight chain alkyl. The prefix "c" means a cycloalkyl. The prefix "(S)" means the S enantiomer and the prefix "(R)" means the R enantiomer. Alkenyl" includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon--carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Alkynyl" includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon--carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Haloalkyl" is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

The term "substituted", as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "appropriate amino acid protecting group" means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of Formulae (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.

The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Syntheses

Some compounds of Formula (1) may be prepared from intermediate compounds of Formula (7), using the procedures outlined in Scheme 1: ##STR21## Compounds of Formula (7) (where Y is O) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80° C. to 250° C. to give products of Formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20° C. to 100C.

Compounds of Formula (8) may be reacted with compounds of Formula R³ H (where R³ is defined as above except R³ is not SH, COR⁷, CO₂ R⁷, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 to 250° C. to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0° C. to 140° C.

Scheme 2 delineates the procedures for converting intermediate compounds of Formula (7) (where Y is S) to some compounds of Formula (1). ##STR22## Compounds of Formula (7) (where Y is S) may be treated with an alkylating agent R¹³ X (where R¹³ is defined as above, except R¹³ is not aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80° C. to 250° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably N,N-di-isopropyl-N-ethyl amine or triethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -80° C. to 100° C.

Compounds of Formula (12) (Formula (1) where R³ is SR¹³) may then be reacted with compounds of Formula R³ H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme 1 above. Alternatively, compounds of Formula (12) (Formula (1) where R³ is SR¹³) may be oxidized to compounds of Formula (13) (Formula (1) where R³ is S(O)_(n) R¹³, n is 1,2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures ranging from -80° C. to 250° C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane or aryl peracids (preferably peracetic acid or m-chloro-perbenzoic acid), dioxirane, oxone, or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbons, preferably acetone), water, alkyl alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof.

The choices of oxidant and solvent are known to those skilled in the art (cf. Uemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 7, 762-769). Preferred reaction temperatures range from -20° C. to 100° C. Compounds of Formula (13) (Formula (1) where R³ is S(O)_(n) R¹³, n is 1,2) may then be reacted with compounds of Formula R³ H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme (1) above.

Compounds of Formula (1), where R³ may be --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --NR⁸ SO₂ R⁷, may be prepared from compounds of Formula (7), where Y is NH, by the procedures depicted in Scheme 3. ##STR23## Reaction of compounds of Formula (7), where Y is NH, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80° C. to 250° C. may afford compounds of Formula (1), where R³ may be --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --NR⁸ SO₂ R⁷. Alkylating agents may include, but are not limited to, C₁ -C₁₀ alkyl -halides, -tosylates, -mesylates or -triflates; C₁ -C₁₀ haloalkyl(1-10 halogens)-halides, -tosylates, -mesylates or -triflates; C₂ -C₈ alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C₃ -C₆ cycloalkyl-halides, tosylates, -mesylates or -triflates; C₄ -C₁₂ cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C₁ -C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C₁ -C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C₁ -C₄ alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C₁ -C₁₀ alkanoyl halides or anhydrides, C₁ -C₁₀ haloalkanoyl halides or anhydrides with 1-10 halogens, C₂ -C₈ alkoxyalkanoyl halides or anhydrides, C₃ -C₆ cycloalkanoyl halides or anhydrides, C₄ -C₁₂ cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C₁ -C₄) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C₁ -C₄) alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C₁ -C₄) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C₁ -C₁₀ alkylsulfonyl halides or anhydrides, C₁ -C₁₀ haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C₂ -C₈ alkoxyalkylsulfonyl halides or anhydrides, C₃ -C₆ cycloalkylsulfinyl halides or anhydrides, C₄ -C₁₂ cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C₁ -C₄ alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C₁ -C₄ alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C₁ -C₄ alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Scheme 4 delineates procedures, which may be employed to prepare intermediate compounds of Formula (7), where Y is O, S and Z is CR². ##STR24## Compounds of the formula ArCH₂ CN are reacted with compounds of the formula R² COR_(b), where R² is defined above and Rb is halogen, cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6 carbons), in the presence of a base in an inert solvent at reaction temperatures ranging from -78° C. to 200° C. to afford compounds of Formula (3). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (3) may be treated with hydrazine-hydrate in the presence of an inert solvent at temperatures ranging from 0° C. to 200° C., preferably 70° C. to 150° C., to produce compounds of Formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of Formula (4) may be reacted with compounds of Formula (5) (where R^(c) is alkyl (1-6 carbons)) in the presence or absence of an acid in the presence of an inert solvent at temperatures ranging from 0° C. to 200° C. to produce compounds of Formula (6). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkanenitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or di-isopropylether) or cyclic ethers such as dioxan or tetrahydrofuran. Preferred temperatures range from ambient temprature to 100° C.

Compounds of Formula (6) may be converted to intermediate compounds of Formula (7) by treatment with compounds C═Y(Rd)₂ (where Y is O or S and R^(d) is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from -50° C. to 200° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures are 0° C. to 150° C.

Intermediate compounds of Formula (7), where Z is N, may be synthesized according the methods outlined in Scheme 5. ##STR25## Compounds of ArCH₂ CN are reacted with compounds of Formula R^(q) CH₂ N₃ (where R^(q) is a phenyl group optionally substituted by H, alkyl (1 to 6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from 0° C. to 200° C. to generate compounds of Formula (9). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from ambient temperature to 100° C.

Compounds of Formula (9) may be treated with a reducing agent in an inert solvent at -100° C. to 100° C. to afford products of Formula (10). Reducing agents include, but are not limited to, (a) hydrogen gas in combination with noble metal catalysts such as Pd-on-carbon, PtO₂, Pt-on-carbon, Rh-on-alumina or Raney nickel, (b) alkali metals (preferably sodium) in combination with liquid ammonia or (c) ceric ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperatures are -50° C. to 60° C. Compounds of Formula (9) are then converted to compounds of Formula (7) (where Z is N) via intermediates of Formula (11) using the reagents and reaction conditions outlined in Scheme 4 for the conversion of compounds of Formula (4) to compounds of Formula (7) (where Z is CR²).

Compounds of Formula (1) may also be prepared from compounds of Formula (7) (where Y is O, S and Z is defined above) as outlined in Scheme 6: ##STR26## Compounds of Formula (7) may be reacted with compounds of Formula R³ H in the presence of a dehydrating agent in an inert solvent at reaction temperatures ranging from 0° C. to 250° C. Dehydrating agents include, but are not limited to, P₂ O₅, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150° C.

Some compounds of Formula (1) (where A is N) may also be prepared by the methods shown in Scheme 7: ##STR27## Intermediate compounds of Formula (14), where Z is defined above, may be reacted with compounds of Formula R³ C(OR_(e))₃, where R_(e) may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0° C. to 250° C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50° C. to 150° C.

Intermediate compounds of Formula (7) may also be synthesized by the reactions displayed in Scheme 8. ##STR28## Compounds of Formula (15), (where Y is OH, SH, NR⁶ R⁷ ; Z is defined above, X is Br, Cl, I, O₃ SCF₃ or B(OR"")₂ and R"" is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from -100° C. to 200° C. Those skilled in the art will recognize that the reagents ArM may be generated in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh₃)₄), palladium halides or alkanoates (such as PdCl₂ (PPh₃)₂ or Pd(OAc)₂) or nickel complexes (such as NiCl₂ (PPh₃)₂). Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -80° C. to 100° C. The choices of M and X are known to those skilled in the art (cf. Imamoto, T., Organocerium Reagents in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 231-250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 211-230; Knight, D. W., Coupling Reactions between sp² Carbon Centers, in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 3, 481-520).

Compounds of Formula (1) may also be prepared using the methods shown in Scheme 9. ##STR29## Compounds of Formula (16), where A, Z, R¹ and R³ are defined above and X is Br, Cl, I, O₃ SCF₃ or B(OR"")₂ and R"" is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from -100° C. to 200° C. Those skilled in the art will recognize that the reagents ArM may be generated in situ (see the above references in Comprehensive Organic Synthesis). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh₃)₄), palladium halides or alkanoates (such as PdCl₂ (PPh₃)₂ or Pd(OAc)₂) or nickel complexes (such as NiCl₂ (PPh₃)₂) Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -80° C. to 100° C.

Intermediate compounds of Formula (7)(where Y is O, S, NH, Z is CR² and R¹, R² and Ar are defined as above) may be prepared as illustrated in Scheme 10. ##STR30## Compounds of Formula (3) may be reacted with compounds of Formula H₂ NNH(C═Y)NH₂, where Y is O, S or NH, in the presence or absence of a base or acid in an inert solvent at temperatures from 0° C. to 250° C. to produce compounds of Formula (17). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 0° C. to 150° C. Compounds of Formula (17) may then be reacted with compounds of Formula R³ C(OR^(e))₃, where R^(e) may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0° C. to 250° C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50° C. to 150° C.

In Scheme 11, the procedures which may be used to convert compounds of Formula (1), where R³ is COR⁷, CO₂ R⁷, NR⁸ COR⁷ and CONR⁶ R⁷, to other compounds of Formula (1), where R³ is CH(OH)R⁷, CH₂ OH, NR⁸ CH₂ R⁷ and CH₂ NR⁶ R⁷ by treatment with a reducing agent in an inert solvent at temperatures ranging from -80° C. to 250° C. ##STR31## Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80° C. to 100° C.

In Scheme 12, the procedures are shown which may be used to convert compounds of Formula (1), where R³ is COR⁷ or CO₂ R⁷, to other compounds of Formula (1), where R³ is C(OH)(R⁷)₂ by treatment with a reagent of Formula R⁷ M in an inert solvent at temperatures ranging from -80° C. to 250° C. ##STR32## M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80° C. to 100° C.

Compounds of Formula (1), where R³ may be --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --NR⁸ SO₂ R⁷, may be synthesized as depicted in Scheme 13. ##STR33## Reaction of compounds of Formula (18), where R and R¹ are defined above, with compounds of Formula (4) or (10) in the presence or absence of base in an inert solvent may produce compounds of Formula (19) at temperatures ranging from -50° C. to 250° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (19) may then be reacted with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80° C. to 250° C. may afford compounds of Formula (1), where R³ may be --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --NR⁸ SO₂ R⁷. Alkylating agents may include, but are not limited to, C₁ -C₁₀ alkyl -halides, -tosylates, -mesylates or -triflates; C₁ -C₁₀ haloalkyl(1-10 halogens)-halides, -tosylates, -mesylates or -triflates; C₂ -C₈ alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C₃ -C₆ cycloalkyl-halides, -tosylates, -mesylates or -triflates; C₄ -C₁₂ cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C₁ -C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C₁ -C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C₁ -C₄ alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C₁ -C₁₀ alkanoyl halides or anhydrides, C₁ -C₁₀ haloalkanoyl halides or anhydrides with 1-10 halogens, C₂ -C₈ alkoxyalkanoyl halides or anhydrides, C₃ -C₆ cycloalkanoyl halides or anhydrides, C₄ -C₁₂ cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C₁ -C₄) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C₁ -C₄) alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C₁ -C₄) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C₁ -C₁₀ alkylsulfonyl halides or anhydrides, C₁ -C₁₀ haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C₂ -C₈ alkoxyalkylsulfonyl halides or anhydrides, C₃ -C₆ cycloalkylsulfonyl halides or anhydrides, C₄ -C₁₂ cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C₁ -C₄ alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C₁ -C₄ alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C₁ -C₄ alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (1), where A is CR and R is defined above, may be synthesized by the methods depicted in Scheme 14. ##STR34## Compounds of Formula (4) or (10) may be treated with compounds of Formula (20), where R¹ and R³ are defined above in the presence or absence of base in an inert solvent at temperatures ranging from 0° C. to 250° C. to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C. Alternatively, compounds of Formula (1) where A is CR and R is defined above, may be synthesized through intermediates (22) and (23).

Compounds of Formula (4) or (10) may be treated with compounds of Formula (21), where R¹ is defined above and R^(e) is alkyl (1-6 carbons), in the presence or absence of base in an inert solvent at temperatures ranging from 0° C. to 250° C. to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C. Compounds of Formula (22) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80° C. to 250° C. to give products of Formula (23) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20° C. to 100° C.

Compounds of Formula (23) may be reacted with compounds of Formula R³ H (where R³ is defined as above except R³ is not SH, COR⁷, CO₂ R⁷, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80° C. to 250° C. to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0° C. to 140° C.

Some compounds of Formula (1) may also be prepared using the methods shown in Scheme 15. ##STR35## A compound of Formula (24) (R_(c) is a lower alkyl group and Ar is defined as above) may be reacted with hydrazine in the presence or absence of an inert solvent to afford an intermediate of Formula (25), where Ar is defined as above. The conditions employed are similar to those used for the preparation of intermediate of Formula (4) from compound of Formula (3) in Scheme 4. Compounds of Formula (25), where A is N, may be reacted with reagents of the formula R¹ C(=NH)OR_(e), where R¹ is defined above and R_(e) is a lower alkyl group) in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of formula Y is C(R_(d))2 (where Y is O or S and R_(d) is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent to give compounds of Formula (27) (where A is N and Y is O, S). The conditions for these transformations are the same as those employed for the conversions of compound of Formula (4) to compound of Formula (7) in Scheme 4.

Alternatively, compounds of Formula (25), where A is CR, may be reacted with compounds of the formula R¹ (C═O)CHR(C═Y)OR_(c) (where R¹ and R are defined as above and R_(c) is a lower alkyl group) to give a compound of Formula (27) (where A is CR) using conditions similar to those employed for the conversion of compounds of Formula (21) to compounds of Formula (22) in Scheme 14. Intermediates of Formula (27) (where Y is O) may be treated with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R³ H or R² H in the presence or absence of a base in an inert solvent to give compounds of Formula (1) (where Z is CR²).

It will be recognized by those skilled in the art that various combinations of halogenating agents, sulfonylating agents, R³ H or R² H may be used in different orders of reaction sequences in Scheme 15 to afford compounds of Formula (1). For example, in some cases, it may be desirable to react compounds with stoichiometric amounts of halogenating agents or sulfonylating agents, react with R² H (or R³ H), then repeat the reaction with halogenating agents or sulfonylating agents and react with R³ H (or R² H) to give compounds of Formula (1). The reaction conditions and reagents used for these conversions are similar to the ones employed for the conversion of intermediate compounds of Formulae (22) to (23) to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N).

Alternatively, compounds of Formula (27) (where Y is S) may be converted to compounds of Formula (1) in Scheme 15. Intermediate compounds of Formula (27) may be alkylated with a compound R^(f) X (where R^(f) is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R³ H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1) may be prepared from compounds of Formula (24), using an alternate route as depicted in Scheme 15. Compounds of Formula (24) may be converted to compounds of Formula (27) via reaction with compounds of formula NH₂ NH(C═NH)NH₂ in the presence or absence of an acid in an inert solvent, followed by reaction with compounds R¹ C(OR_(c))₃ (where R_(c) is lower alkyl and R¹ is defined as above), using the conditions employed for the conversion of compounds of Formulae (3) to (17) to (7) in Scheme 10.

Some compounds of Formula (2) may be prepared by the methods illustrated in Scheme 16. ##STR36## Compounds of Formula (27b) may be treated with various alkylating agents R¹⁴ X (where R¹⁴ is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures of Formula (28). Compounds of Formula (28) (Y is O) may then be converted to compounds of Formula (2) by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R³ H in the presence or absence of a base in an inert solvent to give compounds of Formula (2). The reaction conditions used for these conversions are similar to the ones employed for the conversion of intermediate compounds (22) to (23) to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N). Alternatively, compounds of Formula (28) (Y is S) may be alkylated with a compound R^(f) X (where R^(f) is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R³ H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1), where Z is COH, may be converted to compounds of Formula (2) as illustrated in Scheme 16. Treatment with various alkylating agents R¹⁴ X (where R¹⁴ is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures (2). It will be recognized by one skilled in the art that the methods used in Scheme 16 may also be used to prepare compounds of Formula (1) where Z is COR⁷.

For Scheme 16, the terms "base" and "inert solvent" may have the meanings given below. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20° C. to 100° C.

EXAMPLES

Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on an IBM-Bruker FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemi-ionization (CI) with NH₃ as the carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard 5988A model spectrometer. Melting points were recorded on a Buchi Model 510 melting point apparatus and are uncorrected. Boiling points are uncorrected. All pH determinations during workup were made with indicator paper.

Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general procedures outlined by D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Otherwise, parts and percentages are by weight.

The following examples are provided to describe the invention in further detail. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.

Example 1 Preparation of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one (Formula 7, where Y is O, R₁ is CH₃, Z is C--CH₃, Ar is 2,4-dimethylphenyl)

A. 1-Cyano-1-(2,4-dimethylphenyl)propan-2-one

Sodium pellets (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL) at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then air-dried. The solid was dissolved in water and a 1N HCl solution was added until the pH=5-6. The mixture was extracted with ethyl acetate (3×200 mL); the combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to afford a white solid (45.7 g, 74% yield): NMR (CDCl₃,300 MHz):; CI-MS: 188 (M+H).

B. 5-Amino-4-(2,4-dimethylphenyl)-3-methylpyrazole

A mixture of 1-cyano-1-(2,4-dimethylphenyl)propan-2-one (43.8 g, 0.23 mol), hydrazine-hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0.78 mol) and toluene (500 mL) were stirred at reflux temperature for 18 hours in an apparatus fitted with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was dissolved in 6N HCl and the resulting solution was extracted with ether three times. A concentrated ammonium hydroxide solution was added to the aqueous layer until pH=11. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl₃,300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M+H).

C. 5-Acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acid salt

Ethyl acetamidate hydrochloride (60 g, 0.48 mol) was added quickly to a rapidly stirred mixture of potassium carbonate (69.5 g, 0.50 mol), dichloromethane (120 mL) and water (350 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×120 mL). The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed by simple distillation and the pot residue, a clear pale yellow liquid, (35.0 g) was used without further purification.

Glacial aetic acid (9.7 mL, 0.17 mol) was added to a stirred mixture of 5-amino-4-(2,4-dimethylphenyl)-3-methylpyrazole (34 g, 0.17 mol), ethyl acetamidate (22 g, 0.25 mol) and acetonitrile (500 mL). The resulting reaction mixture was stirred at room temperature for 3 days; at the end of which time, it was concentrated in vacuo to about one-third of its original volume. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. The white solid was dried in vacuo (31.4 g, 61% yield): NMR (DMSO-d₆,300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, J=7, 1), 2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H); CI-MS: 243 (M+H).

D. 2,7-dimethyl-8-(2,4-dimethylphenyl) [1,5-a]-pyrazolo-[1,3,5]-triazin-4 (3H)-one

Sodium pellets (23 g, 1 mol) were added portionwise to ethanol (500 mL) with vigorous stirring. After all the sodium reacted, 5-acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acid salt (31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) were added. The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours. The mix was cooled to room temperature and solvent was removed in vacuo. The residue was dissolved in water and a 1N HCl solution was added slowly until pH=5-6. The aqueous layer was extracted with ethyl acetate three times; the combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a pale tan solid (26 g, 98% yield): NMR (CDCl₃,300 MHz): 7.15(s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H); CI-MS: 269 (M+H).

Example 2 Preparation of 5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazin-7(6H)-one (Formula 7, where Y is O, R₁ is CH₃, Z is N, Ar is 2,4,6-trimethylphenyl)

A. 1-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl₃,300 MHz):7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M+H).

B. 4-(2,4,6-Trimethylphenyl)-5-aminotriazole

Sodium (500 mg, 22 mmol) was added with stirring to a mixture of liquid ammonia (30 mL) and 1-phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole (1.1 g, 3.8 mmol). The reaction mixture was stirred until a dark green color persisted. An ammonium chloride solution (mL) was added and the mixture was stirred while warming to ambient temperature over 16 hours. The residue was treated with a 1M HCl solution and filtered. The aqueous layer was basified with a concentrated ammonium hydroxide solution (pH=9) and then extracted with ethyl acetate three times. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a yellow solid (520 mg), which was homogeneous by thin layer chromatography (ethyl acetate):

NMR (CDCl₃,300 MHz): 6.97 (s, 2H), 3.68-3.50 (br.s, 2H), 2.32 (s, 3H), 2.10 (s, 6H); CI-MS: 203 (M+H).

C. 4-(2,4,6-Trimethylphenyl)-5-acetamidinotriazole, acetic acid salt

A mixture of 4-(2,4,6-trimethylphenyl)-5-aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate 261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient temperature for 4 hours. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. Drying in vacuo afforded a white solid (490 mg, 82% yield): NMR (DMSO-d₆,300 MHz):7.90-7.70 (br s, 0.5H), 7.50-7.20 (br. s, 0.5H), 6.90 (s, 2H), 6.90 (s, 2H), 3.50-3.10 (br s, 3H), 2.30-2.20 (br s, 3H), 2.05 (d, 1H, J=7), 1.96 (s, 6H), 1.87 (s, 6H); CI-MS: 244 (M+H).

D. 5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazin-7(4H)-one

Sodium (368 mg, 16.2 mmol) was added with stirring to ethanol (10 mL) at room temperature. After the sodium had reacted, 4-(2,4,6-trimethylphenyl)-5-acetamidino-triazole, acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. The reaction mixture was stirred at reflux temperature for 5 hours, then cooled to room temperature. The reaction mixture was diluted with water; a 1N HCl solution was added until pH=5-6 and three extractions with ethyl acetate were performed. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a yellow residue. Trituration with ether and filtration afforded a yellow solid (300 mg, 69% yield): NMR (CDCl₃,300 MHz): 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 (s, 6H); CI-MS: 270 (M+H).

Example 3 Preparation of 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Formula 1, where R³ is CH(CHCO₂ CH₃)₂, R₁ is CH₃, Z is C--CH₃, Ar is 2,4-dimethylphenyl)

A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine

A mixture of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38 g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess phosphorus oxychloride was removed in vacuo. The residue was poured onto ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4) gave one fraction (Rf=0.5) Solvent was removed in vacuo to afford a yellow oil (1.0 g, 68% yield): NMR (CDCl₃,300 MHz): 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M+H).

B. 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed with hexanes twice, decanted after each washing and taken up in anhydrous tetrahydrofuran (THF, 1 mL). A solution of diethyl malonate (0.32 g, 2 mmol) in THF (2 mL) was added dropwise over 5 min, during which time vigorous gas evolution ensued. A solution of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine (0.5 g, 1.75 mmol) in THF (2 mL) was added and the reaction mixture was then stirred under a nitrogen atmosphere for 48 hours. The resulting suspension was poured onto water and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Column chromatography (ethyl acetate:hexanes::1:9) afforded, after removal of solvent in vacuo, a pale yellow solid (Rf=0.2, 250 mg, 35% yield): mp 50-52° C.; NMR (CDCl₃, 300 MHz): 12.35 (br.s, 1H, 7.15-7.00 (m, 3H), 4.40 (q, 2H, J=7), 4.30 (q, 2H, J=7), 2.4, 2.35, 2.3, 2.2, 2.1 (5 s, 12H), 1.4 (t, 3H, J=7), 1.35-1.25 (m, 3H); CI-HRMS: Calcd: 411.2032, Found: 411.2023.

Example 6 Preparation of 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Formula 1, where R³ is NHCH(CH₂ OCH₃)₂, R₁ is CH₃, Z is C--CH₃, Ar is 2,4-dichlorophenyl)

A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine

A mixture of 2,7-dimethyl-8-(2,4 dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38 g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess phosphorus oxychloride was removed in vacuo. The residue was poured onto ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4) gave one fraction (Rf=0.5) Solvent was removed in vacuo to afford a yellow oil (1.0 g, 68% yield): NMR (CDCl₃,300 MHz): 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M+H).

B. 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine

A mixture of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Part A, 570 mg, 1.74 mmol), 1,3-dimethoxypropyl-2-aminopropane (25 mg, 2.08 mmol) and ethanol (10 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was poured onto water (25 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo. Column chromatography (CH₂ Cl₂ :CH₃ OH::50:1) afforded one fraction. Removal of solvent in vacuo gave a solid (250 mg, 35% yield): mp 118-120° C.; NMR (CDCl₃,300 MHz): 7.50 (s, 1H), 7.28 (dd, 2H, J=8,1), 6.75 (d, 1H, J=8), 4.70-4.58 (m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H); CI-HRMS: Calcd: 409.1072, Found: 409.1085; Analysis Calcd. for C₁₈ H₂₁ Cl₂ N₅ O₂ : C, 52.69; H, 5.17; N, 17.07; Cl, 17.28; Found: C, 52.82; H, 5.06; N, 16.77; Cl, 17.50.

Using the above procedures and modifications known to one skilled in the art of organic synthesis, the following additional examples of Tables 1-4 may be prepared.

The examples delineated in TABLE 1 may be prepared by the methods outlined in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

                                      TABLE 1                                      __________________________________________________________________________      ##STR37##                                                                     Ex. Z   R.sub.3         Ar          mp (° C.)                           __________________________________________________________________________      6.sup.a                                                                           C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-Cl.sub.2 --Ph                                                                          118-120                                     7.sup.b                                                                           C--Me                                                                              NHCHPr.sub.2    2,4-Cl.sub.2 --Ph                                                                          114-116                                     8.sup.c                                                                           C--Me                                                                              NEtBu           2,4-Cl.sub.2 --Ph                                                                          oil                                         9.sup.d                                                                           C--Me                                                                              NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                               2,4-Cl.sub.2 --Ph                                                                          oil                                         10.sup.e                                                                          C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-Cl.sub.2 --Ph                                                                          oil                                         11.sup.f                                                                          C--Me                                                                              NH-3-heptyl     2,4-Cl.sub.2 --Ph                                                                          90-92                                       12.sup.g                                                                          C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2,4-Cl.sub.2 --Ph                                                                          179-181                                     13.sup.h                                                                          C--Me                                                                              NEt.sub.2       2,4-Cl.sub.2 --Ph                                                                          133-134                                     14.sup.i                                                                          C--Me                                                                              NHCH(CH.sub.2 OEt).sub.2                                                                       2,4-Cl.sub.2 --Ph                                                                          oil                                         15.sup.j                                                                          C--Me                                                                              NH-3-pentyl     2,4-Cl.sub.2 --Ph                                                                          139-140                                     16.sup.k                                                                          C--Me                                                                              NMePh           2,4-Cl.sub.2 --Ph                                                                          60-62                                       17.sup.l                                                                          C--Me                                                                              NPr.sub.2       2,4-Cl.sub.2 --Ph                                                                          oil                                         18.sup.m                                                                          C--Me                                                                              NH-3-hexyl      2,4-Cl.sub.2 --Ph                                                                          130--132                                    19 C--Me                                                                              morpholino      2,4-Cl.sub.2 --Ph                                       20 C--Me                                                                              N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                            2,4-Cl.sub.2 --Ph                                       21 C--Me                                                                              NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                  2,4-Cl.sub.2 --Ph                                       22 C--Me                                                                              NH-4-tetrahydropyranyl                                                                         2,4-Cl.sub.2 --Ph                                       23 C--Me                                                                              NH-cyclopentyl  2,4-Cl.sub.2 --Ph                                       24 C--Me                                                                              1,2,3,4-tetrahydro-                                                                            2,4-Cl.sub.2 --Ph                                              isoquinolinyl                                                           25 C--Me                                                                              CH.sub.2 -(1,2,3,4-tetrahydro-                                                                 2,4-Cl.sub.2 --Ph                                              isoquinolinyl)                                                          26.sup.n                                                                          C--Me                                                                              OEt             2,4-Cl.sub.2 --Ph                                                                          141-143                                     27 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2,4-Cl.sub.2 --Ph                                       28 C--Me                                                                              OCH.sub.2 Ph    2,4-Cl.sub.2 --Ph                                       29 C--Me                                                                              O-3-pentyl      2,4-Cl.sub.2 --Ph                                       30 C--Me                                                                              SEt             2,4-Cl.sub.2 --Ph                                       31 C--Me                                                                              S(O)Et          2,4-Cl.sub.2 --Ph                                       32 C--Me                                                                              SO.sub.2 Et     2,4-Cl.sub.2 --Ph                                       33 C--Me                                                                              CH(CO.sub.2 Et).sub.2                                                                          2,4-Cl.sub.2 --Ph                                       34 C--Me                                                                              C(Et)(CO.sub.2 Et).sub.2                                                                       2,4-Cl.sub.2 --Ph                                       35 C--Me                                                                              CH(Et)CH.sub.2 OH                                                                              2,4-Cl.sub.2 --Ph                                       36 C--Me                                                                              CH(Et)CH.sub.2 OMe                                                                             2,4-Cl.sub.2 --Ph                                       37 C--Me                                                                              CONMe.sub.2     2,4-Cl.sub.2 --Ph                                       38 C--Me                                                                              COCH.sub.3      2,4-Cl.sub.2 --Ph                                       39 C--Me                                                                              CH(OH)CH.sub.3  2,4-Cl.sub.2 --Ph                                       40 C--Me                                                                              C(OH)Ph-3-pyridyl                                                                              2,4-Cl.sub.2 --Ph                                       41 C--Me                                                                              Ph              2,4-Cl.sub.2 --Ph                                       42 C--Me                                                                              2-CF.sub.3 --Ph 2,4-Cl.sub.2 --Ph                                       43 C--Me                                                                              2-Ph--Ph        2,4-Cl.sub.2 --Ph                                       44 C--Me                                                                              3-pentyl        2,4-Cl.sub.2 --Ph                                       45 C--Me                                                                              cyclobutyl      2,4-Cl.sub.2 --Ph                                       46 C--Me                                                                              3-pyridyl       2,4-Cl.sub.2 --Ph                                       47 C--Me                                                                              CH(Et)CH.sub.2 CONMe.sub.2                                                                     2,4-Cl.sub.2 --Ph                                       48 C--Me                                                                              CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                              2,4-Cl.sub.2 --Ph                                       49.sup.o                                                                          C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4,6-Me.sub.3 --Ph                                                                        125-127                                     50 C--Me                                                                              NHCHPr.sub.2    2,4,6-Me.sub.3 --Ph                                     51 C--Me                                                                              NEtBu           2,4,6-Me.sub.3 --Ph                                     52 C--Me                                                                              NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                               2,4,6-Me.sub.3 --Ph                                     53.sup.ae                                                                         C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4,6-Me.sub.3 --Ph                                                                        123-124                                     54 C--Me                                                                              NH-3-heptyl     2,4,6-Me.sub.3 --Ph                                     55.sup.ac                                                                         C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2,4,6-Me.sub.3 --Ph                                                                        145-146                                     56.sup.ah                                                                         C--Me                                                                              NEt.sub.2       2,4,6-Me.sub.3 --Ph                                                                        88-90                                       57.sup.ai                                                                         C--Me                                                                              NHCH(CH.sub.2 OEt).sub.2                                                                       2,4,6-Me.sub.3 --Ph                                                                        132-134                                     58.sup.ad                                                                         C--Me                                                                              NH-3-pentyl     2,4,6-Me.sub.3 --Ph                                                                        134-135                                     59 C--Me                                                                              NMePh           2,4,6-Me.sub.3 --Ph                                     60 C--Me                                                                              NPr.sub.2       2,4,6-Me.sub.3 --Ph                                     61 C--Me                                                                              NH-3-hexyl      2,4,6-Me.sub.3 --Ph                                     62 C--Me                                                                              morpholino      2,4,6-Me.sub.3 --Ph                                     63 C--Me                                                                              N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                            2,4,6-Me.sub.3 --Ph                                     64 C--Me                                                                              NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                  2,4,6-Me.sub.3 --Ph                                     65 C--Me                                                                              NH-4-tetrahydropyranyl                                                                         2,4,6-Me.sub.3 --Ph                                     66 C--Me                                                                              NH-cyclopentyl  2,4,6-Me.sub.3 --Ph                                     67 C--Me                                                                              1,2,3,4-tetrahydro-                                                                            2,4,6-Me.sub.3 --Ph                                            isoquinolinyl                                                           68 C--Me                                                                              CH.sub.2 -(1,2,3,4-tetrahydro-                                                                 2,4,6-Me.sub.3 --Ph                                            isoquinolinyl)                                                          69 C--Me                                                                              OEt             2,4,6-Me.sub.3 --Ph                                     70 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2,4,6-Me.sub.3 --Ph                                     71 C--Me                                                                              OCH.sub.2 Ph    2,4,6-Me.sub.3 --Ph                                     72 C--Me                                                                              O-3-pentyl      2,4,6-Me.sub.3 --Ph                                     73 C--Me                                                                              SEt             2,4,6-Me.sub.3 --Ph                                     74 C--Me                                                                              S(O)Et          2,4,6-Me.sub.3 --Ph                                     75 C--Me                                                                              SO.sub.2 Et     2,4,6-Me.sub.3 --Ph                                     76 C--Me                                                                              CH(CO.sub.2 Et).sub.2                                                                          2,4,6-Me.sub.3 --Ph                                     77 C--Me                                                                              C(Et)(CO.sub.2 Et).sub.2                                                                       2,4,6-Me.sub.3 --Ph                                     78 C--Me                                                                              CH(Et)CH.sub.2 OH                                                                              2,4,6-Me.sub.3 --Ph                                     79 C--Me                                                                              CH(Et)CH.sub.2 OMe                                                                             2,4,6-Me.sub.3 --Ph                                     80 C--Me                                                                              CONMe.sub.2     2,4,6-Me.sub.3 --Ph                                     81 C--Me                                                                              COCH.sub.3      2,4,6-Me.sub.3 --Ph                                     82 C--Me                                                                              CH(OH)CH.sub.3  2,4,6-Me.sub.3 --Ph                                     83 C--Me                                                                              C(OH)Ph-3-pyridyl                                                                              2,4,6-Me.sub.3 --Ph                                     84 C--Me                                                                              Ph              2,4,6-Me.sub.3 --Ph                                     85 C--Me                                                                              2-CF.sub.3 --Ph 2,4,6-Me.sub.3 --Ph                                     86 C--Me                                                                              2-Ph--Ph        2,4,6-Me.sub.3 --Ph                                     87 C--Me                                                                              3-pentyl        2,4,6-Me.sub.3 --Ph                                     88 C--Me                                                                              cyclobutyl      2,4,6-Me.sub.3 --Ph                                     89 C--Me                                                                              3-pyridyl       2,4,6-Me.sub.3 --Ph                                     90 C--Me                                                                              CH(Et)CH.sub.2 CONMe.sub.2                                                                     2,4,6-Me.sub.3 --Ph                                     91 C--Me                                                                              CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                              2,4,6-Me.sub.3 --Ph                                     92.sup.p                                                                          C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-Me.sub.2 --Ph                                                                          44-45                                       93.sup.q                                                                          C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-Me.sub.2 --Ph                                                                          oil                                         94.sup.r                                                                          C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2,4-Me.sub.2 --Ph                                                                          102-104                                     95.sup.s                                                                          C--Me                                                                              NH-3-pentyl     2,4-Me.sub.2 --Ph                                                                          102-104                                     96.sup.t                                                                          C--Me                                                                              NEt.sub.2       2,4-Me.sub.2 --Ph                                                                          oil                                         97.sup.u                                                                          C--Me                                                                              N(CH.sub.2 CN).sub.2                                                                           2,4-Me.sub.2 --Ph                                                                          148-150                                    130 C--Me                                                                              CH(Et)CH.sub.2 OH                                                                              2,4-Me.sub.2 --Ph                                      131 C--Me                                                                              CH(Et)CH.sub.2 OMe                                                                             2,4-Me.sub.2 --Ph                                      132 C--Me                                                                              CH(Et)CH.sub.2 OEt                                                                             2,4-Me.sub.2 --Ph                                      133 C--Me                                                                              CONMe.sub.2     2,4-Me.sub.2 --Ph                                      134 C--Me                                                                              COCH.sub.3      2,4-Me.sub.2 --Ph                                      135 C--Me                                                                              CH(OH)CH.sub.3  2,4-Me.sub.2 --Ph                                      136 C--Me                                                                              C(OH)Ph-3-pyridyl                                                                              2,4-Me.sub.2 --Ph                                      137 C--Me                                                                              Ph              2,4-Me.sub.2 --Ph                                      138 C--Me                                                                              2-CF.sub.3 --Ph 2,4-Me.sub.2 --Ph                                      139 C--Me                                                                              2-Ph--Ph        2,4-Me.sub.2 --Ph                                      140 C--Me                                                                              3-pentyl        2,4-Me.sub.2 --Ph                                      141 C--Me                                                                              cyclobutyl      2,4-Me.sub.2 --Ph                                      142 C--Me                                                                              3-pyridyl       2,4-Me.sub.2 --Ph                                      143 C--Me                                                                              CH(Et)CH.sub.2 CONMe.sub.2                                                                     2,4-Me.sub.2 --Ph                                      144 C--Me                                                                              CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                              2,4-Me.sub.2 --Ph                                      145.sup.bc                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Me-4-MeO--Ph                                                                             45-46                                      146.sup.bd                                                                         C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Me-4-MeO--Ph                                                                             oil                                        147.sup.be                                                                         C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Me-4-MeO--Ph                                                                             86-88                                      148.sup.bf                                                                         C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Me-4-MeO--Ph                                                                             oil                                        149 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Me-4-MeO--Ph                                         150.sup.af                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4-MeO--Ph                                                                             88-90                                      151.sup.al                                                                         C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4-MeO--Ph                                                                             oil                                        152.sup.ag                                                                         C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Br-4-MeO--Ph                                                                             95-97                                      153 C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Br-4-MeO--Ph                                         154 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Br-4-MeO--Ph                                         155 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Me-4-NMe.sub.2 --Ph                                  156 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Me-4-NMe.sub.2 --Ph                                                                      oil                                        157 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Me-4-NMe.sub.2 --Ph                                  158 C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Me-4-NMe.sub.2 --Ph                                  159 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Me-4-NMe.sub.2 --Ph                                  160 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4-NMe.sub.2 --Ph                                  161 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4-NMe.sub.2 --Ph                                  162 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Br-4-NMe.sub.2 --Ph                                  163 C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Br-4-NMe.sub.2 --Ph                                  164 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Br-4-NMe.sub.2 --Ph                                  165 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4-i-Pr--Ph                                        166 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4-i-Pr--Ph                                        167 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Br-4-i-Pr--Ph                                        168 C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Br-4-i-Pr--Ph                                        169 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Br-4-i-Pr--Ph                                        170 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4-Me--Ph                                          171 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4-Me--Ph                                          172 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Br-4-Me--Ph                                          173 C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Br-4-Me--Ph                                          174 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Br-4-Me--Ph                                          175.sup.ar                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Me-4-Br--Ph                                                                              108-109                                    176 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Me-4-Br--Ph                                          177 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Me-4-Br--Ph                                          178 C--Me                                                                              N(Pr)CH.sub.2 CH.sub.2 CN                                                                      2-Me-4-Br--Ph                                          179 C--Me                                                                              OCH(Et)CH.sub.2 OMe                                                                            2-Me-4-Br--Ph                                          180 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Cl-4,6-Me.sub.2 --Ph                                 181 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Cl-4,6-Me.sub.2 --Ph                                 182 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-Br-2,6-(Me).sub.2 --Ph                               183 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-Br-2,6-(Me).sub.2 --Ph                               184 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-i-Pr-2-SMe--Ph                                       185 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-i-Pr-2-SMe--Ph                                       186 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4-CF.sub.3 --Ph                                   187 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4-CF.sub.3 --Ph                                   188 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4,6-(MeO).sub.2 --Ph                              189 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4,6-(MeO).sub.2 --Ph                              190 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Cl-4,6-(MeO).sub.2 --Ph                              191 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Cl-4,6-(MeO).sub.2 --Ph                              192 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,6-(Me).sub.2 -4-SMe--Ph                              193 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,6-(Me).sub.2 -4-SMe--Ph                              194 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-(COMe)-2-Br--Ph                                      195 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-(COMe)-2-Br--Ph                                      196 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4,6-Me.sub.3 -pyrid-3-yl                             197 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4,6-Me.sub.3 -pyrid-3-yl                             198 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-(Br).sub.2 --Ph                                    199 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-(Br).sub.2 --Ph                                    200 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-i-Pr-2-SMe--Ph                                       201 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-i-Pr-2-SMe--Ph                                       202 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-i-Pr-2-SO.sub.2 Me--Ph                               203 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-i-Pr-2-SO.sub.2 Me--Ph                               204 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,6-(Me).sub.2 -4-SMe--Ph                              205 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,6-(Me).sub.2 -4-SMe--Ph                              206 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,6-(Me).sub.2 -4-SO.sub.2 Me--Ph                      207 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,6-(Me).sub.2 -4-SO.sub.2 Me--Ph                      208 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-I-4-i-Pr--Ph                                         209 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-I-4-i-Pr--Ph                                         210 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4-N(Me).sub.2 -6-MeO--Ph                          211 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4-N(Me).sub.2 -6-MeO--Ph                          212 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-[SMe]2--Ph                                         213 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-[SMe]2--Ph                                         214 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-[SO.sub.2 Me]2--Ph                                 215 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-[SO.sub.2 Me]2--Ph                                 216 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-i-Pr-2-SMe--Ph                                       217 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-i-Pr-2-SMe--Ph                                       218 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       4-i-Pr-2-SO.sub.2 Me--Ph                               219 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 4-i-Pr-2-SO.sub.2 Me--Ph                               220 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-N(Me).sub.2 -4-Me--Ph                                221 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-N(Me).sub.2 -4-Me--Ph                                222 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-MeS-4,6-(Me).sub.2 --Ph                              223 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-MeS-4,6-(Me).sub.2 --Ph                              224 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-(CH.sub.3 CO)-4,6-(Me).sub.2 --Ph                    225 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-(CH.sub.3 CO)-4,6-(Me).sub.2 --Ph                    226 H   NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-Me.sub.2 --Ph                                      227 H   NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-Me.sub.2 --Ph                                      228 CF3 N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-Me.sub.2 --Ph                                      229 CF3 N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-Me.sub.2 --Ph                                      230 N   NHCH(CH.sub.2 OMe).sub.2                                                                       2,4,6-Me.sub.3 --Ph                                    231 N   NHCHPr.sub.2    2,4,6-Me.sub.3 --Ph                                    232 N   NEtBu           2,4,6-Me.sub.3 --Ph                                    233 N   NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                               2,4,6-Me.sub.3 --Ph                                    234 N   N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4,6-Me.sub.3 --Ph                                    235 N   NH-3-heptyl     2,4,6-Me.sub.3 --Ph                                    236 N   NHCH(Et)CH.sub.2 OMe                                                                           2,4,6-Me.sub.3 --Ph                                    237 N   NEt.sub.2       2,4,6-Me.sub.3 --Ph                                    238 N   NHCH(CH.sub.2 OEt).sub.2                                                                       2,4,6-Me.sub.3 --Ph                                    239 N   NH-3-pentyl     2,4,6-Me.sub.3 --Ph                                    240 N   NMePh           2,4,6-Me.sub.3 --Ph                                    241 N   NPr.sub.2       2,4,6-Me.sub.3 --Ph                                    242 N   NH-3-hexyl      2,4,6-Me.sub.3 --Ph                                    243 N   morpholino      2,4,6-Me.sub.3 --Ph                                    244 N   N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                            2,4,6-Me.sub.3 --Ph                                    245 N   NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                  2,4,6-Me.sub.3 --Ph                                    246 N   NH-4-tetrahydropyranyl                                                                         2,4,6-Me.sub.3 --Ph                                    247 N   NH-cyclopentyl  2,4,6-Me.sub.3 --Ph                                    248 N   1,2,3,4-tetrahydro-                                                                            2,4,6-Me.sub.3 --Ph                                            isoquinolinyl                                                          249 N   CH.sub.2 -(1,2,3,4-tetrahydro-                                                                 2,4,6-Me.sub.3 --Ph                                            isoquinolinyl)                                                         250 N   OEt             2,4,6-Me.sub.3 --Ph                                    251 N   OCH(Et)CH.sub.2 OMe                                                                            2,4,6-Me.sub.3 --Ph                                    252 N   OCH.sub.2 Ph    2,4,6-Me.sub.3 --Ph                                    253 N   O-3-pentyl      2,4,6-Me.sub.3 --Ph                                    254 N   SEt             2,4,6-Me.sub.3 --Ph                                    255 N   S(O)Et          2,4,6-Me.sub.3 --Ph                                    256 N   SO.sub.2 Et     2,4,6-Me.sub.3 --Ph                                    257 N   CH(CO.sub.2 Et).sub.2                                                                          2,4,6-Me.sub.3 --Ph                                    258 N   C(Et) (CO.sub.2 Et).sub.2                                                                      2,4,6-Me.sub.3 --Ph                                    259 N   CH(Et)CH.sub.2 OH                                                                              2,4,6-Me.sub.3 --Ph                                    260 N   CH(Et)CH.sub.2 OMe                                                                             2,4,6-Me.sub.3 --Ph                                    261 N   CONMe.sub.2     2,4,6-Me.sub.3 --Ph                                    262 N   COCH.sub.3      2,4,6-Me.sub.3 --Ph                                    263 N   CH(OH)CH.sub.3  2,4,6-Me.sub.3 --Ph                                    264 N   C(OH)Ph-3-pyridyl                                                                              2,4,6-Me.sub.3 --Ph                                    265 N   Ph              2,4,6-Me.sub.3 --Ph                                    266 N   2-CF.sub.3 --Ph 2,4,6-Me.sub.3 --Ph                                    267 N   2-Ph--Ph        2,4,6-Me.sub.3 --Ph                                    268 N   3-pentyl        2,4,6-Me.sub.3 --Ph                                    269 N   cyclobutyl      2,4,6-Me.sub.3 --Ph                                    270 N   3-pyridyl       2,4,6-Me.sub.3 --Ph                                    271 N   CH(Et)CH.sub.2 CONMe.sub.2                                                                     2,4,6-Me.sub.3 --Ph                                    272 N   CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                              2,4,6-Me.sub.3 --Ph                                    273 N   NHCH(CH.sub.2 OMe).sub.2                                                                       2,4-Me.sub.2 --Ph                                      274 N   NHCHPr.sub.2    2,4-Me.sub.2 --Ph                                      275 N   NEtBu           2,4-Me.sub.2 --Ph                                      276 N   NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                               2,4-Me.sub.2 --Ph                                      277 N   N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,4-Me.sub.2 --Ph                                      278 N   NH-3-heptyl     2,4-Me.sub.2 --Ph                                      279 N   NHCH(Et)CH.sub.2 OMe                                                                           2,4-Me.sub.2 --Ph                                      280 N   NEt.sub.2       2,4-Me.sub.2 --Ph                                      281 N   NHCH(CH.sub.2 OEt).sub.2                                                                       2,4-Me.sub.2 --Ph                                      282 N   NH-3-pentyl     2,4-Me.sub.2 --Ph                                      283 N   NMePh           2,4-Me.sub.2 --Ph                                      284 N   NPr.sub.2       2,4-Me.sub.2 --Ph                                      285 N   NH-3-hexyl      2,4-Me.sub.2 --Ph                                      286 N   morpholino      2,4-Me.sub.2 --Ph                                      287 N   N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                            2,4-Me.sub.2 --Ph                                      288 N   NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                  2,4-Me.sub.2 --Ph                                      289 N   NH-4-tetrahydropyranyl                                                                         2,4-Me.sub.2 --Ph                                      290 N   NH-cyclopentyl  2,4-Me.sub.2 --Ph                                      291 N   1,2,3,4-tetrahydro-                                                                            2,4-Me.sub.2 --Ph                                              isoquinolinyl                                                          292 N   CH.sub.2 -(1,2,3,4-tetrahydro-                                                                 2,4-Me.sub.2 --Ph                                              isoquinolinyl)                                                         293 N   OEt             2,4-Me.sub.2 --Ph                                      294 N   OCH(Et)CH.sub.2 OMe                                                                            2,4-Me.sub.2 --Ph                                      295 N   OCH.sub.2 Ph    2,4-Me.sub.2 --Ph                                      296 N   O-3-pentyl      2,4-Me.sub.2 --Ph                                      297 N   SEt             2,4-Me.sub.2 --Ph                                      298 N   S(O)Et          2,4-Me.sub.2 --Ph                                      299 N   SO.sub.2 Et     2,4-Me.sub.2 --Ph                                      300 N   CH(CO.sub.2 Et).sub.2                                                                          2,4-Me.sub.2 --Ph                                      301 N   C(Et)(CO.sub.2 Et).sub.2                                                                       2,4-Me.sub.2 --Ph                                      302 N   CH(Et)CH.sub.2 OH                                                                              2,4-Me.sub.2 --Ph                                      303 N   CH(Et)CH.sub.2 OMe                                                                             2,4-Me.sub.2 --Ph                                      304 N   CONMe.sub.2     2,4-Me.sub.2 --Ph                                      305 N   COCH.sub.3      2,4-Me.sub.2 --Ph                                      306 N   CH(OH)CH.sub.3  2,4-Me.sub.2 --Ph                                      307 N   C(OH)Ph-3-pyridyl                                                                              2,4-Me.sub.2 --Ph                                      308 N   Ph              2,4-Me.sub.2 --Ph                                      309 N   2-CF.sub.3 --Ph 2,4-Me.sub.2 --Ph                                      310 N   2-Ph--Ph        2,4-Me.sub.2 --Ph                                      311 N   3-pentyl        2,4-Me.sub.2 --Ph                                      312 N   cyclobutyl      2,4-Me.sub.2 --Ph                                      313 N   3-pyridyl       2,4-Me.sub.2 --Ph                                      314 N   CH(Et)CH.sub.2 CONMe.sub.2                                                                     2,4-Me.sub.2 --Ph                                      315 N   CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                              2,4-Me.sub.2 --Ph                                      316.sup.an                                                                         C--Me                                                                              NEt.sub.2       2-Br-4-MeO--Ph                                                                             oil                                        317.sup.am                                                                         C--Me                                                                              NH-3-pentyl     2-Br-4-MeO--Ph                                                                             oil                                        318.sup.aj                                                                         C--Me                                                                              NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                        2,4,6-Me.sub.3 --Ph                                                                        101-103                                    319.sup.ao                                                                         C--Me                                                                              NH(c-C.sub.3 H.sub.5)                                                                          2,4-Me.sub.2 --Ph                                                                          oil                                        320.sup.ak                                                                         C--Me                                                                              morpholino      2,4,6-Me.sub.3 --Ph                                                                        139-141                                    321.sup.ap                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-CN-4-Me--Ph                                                                              152-153                                    322.sup.aq                                                                         C--Me                                                                              N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                       2,4,6-Me.sub.3 --Ph                                                                        149-151                                    324.sup.as                                                                         C--Me                                                                              NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                        2-Me-4-Br--Ph                                                                              115-117                                    325.sup.at                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2,5-Me.sub.2 -4-MeO--Ph                                                                    55-57                                      326.sup.au                                                                         C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2,5-Me.sub.2 -4-MeO--Ph                                                                     72                                        327.sup.av                                                                         C--Me                                                                              NH-3-pentyl     2,5-Me.sub.2 -4-MeO--Ph                                                                    45-47                                      328.sup.aw                                                                         C--Me                                                                              NEt.sub.2       2,5-Me.sub.2 -4-MeO--Ph                                                                    oil                                        329.sup.ax                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Cl-4-MePh 80-81                                      330.sup.ay                                                                         C--Me                                                                              NCH(Et)CH.sub.2 OMe                                                                            2-Cl-4-MePh 77-79                                      331.sup.az                                                                         C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Cl-4-MePh oil                                        332.sup.ba                                                                         C--Me                                                                              (S)--NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                   2-Cl-4-MePh 139-140                                    333.sup.bb                                                                         C--Me                                                                              N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                       2,5-Me.sub.2 -4-MeOPh                                                                      120-122                                    334.sup.bg                                                                         C--Me                                                                              NEt.sub.2       2-Me-4-MeOPh                                                                               oil                                        335.sup.bh                                                                         C--Me                                                                              OEt             2-Me-4-MeOPh                                                                               oil                                        336.sup.bi                                                                         C--Me                                                                              (S)--NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                   2-Me-4-MeOPh                                                                               oil                                        337.sup.bj                                                                         C--Me                                                                              N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                       2-Me-4-MeOPh                                                                               129                                        338.sup.bk                                                                         C--Me                                                                              NHCH(CH.sub.2 CH.sub.2 OEt).sub.2                                                              2-Me-4-MeOPh                                                                               amorph.                                    339 C--Me                                                                              N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                       2,4-Cl.sub.2 --Ph                                                                          109-110                                    340 C--Me                                                                              (S)-NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                    2,4-Cl.sub.2 --Ph                                                                          93-94                                      341 C--Me                                                                              NH-3-pentyl     2-Me-4-BrPh 118-119                                    342 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Me-4-BrPh oil                                        343 C--Me                                                                              NHCH(CH.sub.2 -iPr)CH.sub.2 OMe                                                                2,4-Me.sub.2 --Ph                                                                          oil                                        344 C--Me                                                                              NHCH(Pr)CH.sub.2 OMe                                                                           2,4-Me.sub.2 --Ph                                                                          94-95                                      345 C--Me                                                                              NHCH(Et)CH.sub.2 OEt                                                                           2,4-Me.sub.2 --Ph                                                                          76-77                                      346 C--Me                                                                              NHCH(CH.sub.2 OMe)CH.sub.2 CH.sub.2 OMe                                                        2-Me-4-Me.sub.2 NPh                                                                        oil                                        347 C--Me                                                                              NEt.sub.2       2-Me-4-ClPh oil                                        348 C--Me                                                                              NH-3-pentyl     2-Me-4-ClPh 122-124                                    349 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Me-4-ClPh oil                                        350 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Me-4-ClPh 122-123                                    351 C--Me                                                                              NEt.sub.2       2-Me-4-ClPh oil                                        352 C--Me                                                                              NEt.sub.2       2-Cl-4-MePh oil                                        353 C--Me                                                                              NH-3-pentyl     2-Cl-4-MePh 120-121                                    354 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Cl-4-MeOPh                                           355.sup.bl                                                                         C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Cl-4-MeOPh                                                                               oil                                        356.sup.bm                                                                         C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Cl-4-MeOPh                                                                               108-110                                    357.sup.bn                                                                         C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Cl-4-MeOPh                                                                               127-129                                    358.sup.bo                                                                         C--Me                                                                              NEt.sub.2       2-Cl-4-MeOPh                                                                               oil                                        359.sup.bp                                                                         C--Me                                                                              NH-3-pentyl     2-Cl-4-MeOPh                                                                               77-79                                      360 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Cl-4-MeOPh                                           361 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Cl-4-MeOPh                                           362 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Br-4-MeOPh                                           363 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Br-4-MeOPh                                           364 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Me-4-MeOPh                                           365 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Me-4-MeOPh                                           366 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Cl-4,5-(MeO).sub.2 Ph                                367 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Cl-4,5-(MeO).sub.2 Ph                                368 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Cl-4,5-(MeO).sub.2 Ph                                369 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Cl-4,5-(MeO).sub.2 Ph                                370 C--Me                                                                              NEt.sub.2       2-Cl-4,5-(MeO).sub.2 Ph                                371 C--Me                                                                              NH-3-pentyl     2-Cl-4,5-(MeO).sub.2 Ph                                372 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Cl-4,5-(MeO).sub.2 Ph                                373 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Cl-4,5-(MeO).sub.2 Ph                                374.sup.bq                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Br-4,5-(MeO).sub.2 Ph                                                                    137-138                                    375 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Br-4,5-(MeO).sub.2 Ph                                376.sup.br                                                                         C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Br-4,5-(MeO).sub.2 Ph                                                                    147-148                                    377 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Br-4,5-(MeO).sub.2 Ph                                378.sup.bs                                                                         C--Me                                                                              NEt.sub.2       2-Br-4,5-(MeO).sub.2 Ph                                                                    52-58                                      379 C--Me                                                                              NH-3-pentyl     2-Br-4,5-(MeO).sub.2 Ph                                380 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Br-4,5-(MeO).sub.2 Ph                                381 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Br-4,5-(MeO).sub.2 Ph                                382 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Cl-4,6-(MeO).sub.2 Ph                                383 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Cl-4,6-(MeO).sub.2 Ph                                384 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Cl-4,6-(MeO).sub.2 Ph                                385 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Cl-4,6-(MeO).sub.2 Ph                                386 C--Me                                                                              NEt.sub.2       2-Cl-4,6-(MeO).sub.2 Ph                                387 C--Me                                                                              NH-3-pentyl     2-Cl-4,6-(MeO).sub.2 Ph                                388 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Cl-4,6-(MeO).sub.2 Ph                                389 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Cl-4,6-(MeO).sub.2 Ph                                390 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-Me-4,6-(MeO).sub.2 Ph                                391 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-Me-4,6-(MeO).sub.2 Ph                                392 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-Me-4,6-(MeO).sub.2 Ph                                393 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Me-4,6-(MeO).sub.2 Ph                                395 C--Me                                                                              NEt.sub.2       2-Me-4,6-(MeO).sub.2 Ph                                396 C--Me                                                                              NH-3-pentyl     2-Me-4,6-(MeO).sub.2 Ph                                397 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Me-4,6-(MeO).sub.2 Ph                                398 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Me-4,6-(MeO).sub.2 Ph                                399 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Br-4,6-(MeO).sub.2 Ph                                400 C--Me                                                                              NEt.sub.2       2-Br-4,6-(MeO).sub.2 Ph                                401 C--Me                                                                              NH-3-pentyl     2-Br-4,6-(MeO).sub.2 Ph                                402 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Br-4,6-(MeO).sub.2 Ph                                403 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Br-4,6-(MeO).sub.2 Ph                                404 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-Me-4-MeOPh                                           405 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-Me-4-MeOPh                                           406 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-MeO-4-MePh                                           407 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-MeO-4-MePh                                           408 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-MeO-4-MePh                                           409 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-MeO-4-MePh                                           410 C--Me                                                                              NEt.sub.2       2-MeO-4-MePh                                           411 C--Me                                                                              NH-3-pentyl     2-MeO-4-MePh                                           412 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-MeO-4-MePh                                           413 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-MeO-4-MePh                                           414 C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-MeO-4-MePh                                           415 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-MeO-4-MePh                                           416 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-MeO-4-MePh                                           417 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-MeO-4-MePh                                           418 C--Me                                                                              NEt.sub.2       2-MeO-4-MePh                                           419 C--Me                                                                              NH-3-pentyl     2-MeO-4-MePh                                           420 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-MeO-4-MePh                                           421 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-MeO-4-MePh                                           423.sup.bt                                                                         C--Me                                                                              NHCH(CH.sub.2 OMe).sub.2                                                                       2-MeO-4-ClPh                                                                               oil                                        424 C--Me                                                                              N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                 2-MeO-4-ClPh                                           425 C--Me                                                                              NHCH(Et)CH.sub.2 OMe                                                                           2-MeO-4-ClPh                                           426 C--Me                                                                              N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                    2-MeO-4-ClPh                                           427 C--Me                                                                              NEt.sub.2       2-MeO-4-ClPh                                           428 C--Me                                                                              NH-3-pentyl     2-MeO-4-ClPh                                           429 C--Me                                                                              NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                  2-MeO-4-ClPh                                           430 C--Me                                                                              NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                  2-MeO-4-ClPh                                           __________________________________________________________________________     NOTES FOR TABLE 1:                                                             .sup.a Analysis Calcd: C, 52.69, H, 5.17, N, 17.07, Cl, 17.28; Found: C,       52.82, H, 5.06, N, 16.77,                                                      Cl, 17.50.                                                                     .sup.b CI-HRMS: Calcd: 406.1565, Found: 405.1573(M+H); Analysis Calcd: C:      59.11; H: 6.20; N:                                                             17.23; Cl: 17.45; Found: C: 59.93; H: 6.34; N: 16.50; Cl: 16.95;               NMR(CDCl.sub.3, 300 MHz): 0.95(t,                                              J=8, 4H), 1.30-1.40(m, 4H), 1.50-1.75(m, 4H), 2.35(s, 3H), 2.48(s, 3H),        4.30-4.45(m, 1H),                                                              6.15(d, J=8, 1H), 7.30(s, 2H), 7.50(s, 1H)                                     .sup.c CI-HRMS: Calcd: 392.1409, Found: 392.1388(M+H); NMR(CDCl.sub.3,         300 MHz): 1.00(t, J=8, 3H),                                                    1.35(t, J=8, 3H), 1.41(q, J=8, 2H), 1.65-1.85(m, 2H), 2.30(s, 3H),             2.40(s, 3H), 3.85-4.20(m,                                                      4H), 7.30 (s, 2H), 7.50(s, 1H).                                                .sup.d CI-HRMS: Calcd: 404.1409, Found: 404.1408(M+H); NMR(CDCl.sub.3,         300 MHz):                                                                      0.35-0.45(m, 2H), 0.52-0.62(m, 2H), 0.98(t, J=8, 3H), 1.70-1.90(m, 2H),        2.30(s, 3H), 2.40(s, 3H), 3.85-4.02(m, 2H), 4.02-4.20(m, 2H), 7.30(s,          2H), 7.50(s, 1H).                                                              .sup.e CI-HRMS: Calcd: 424.1307, Found: 424.1307(M+H); NMR(CDCl.sub.3,         300 MHz): 2.28(s, 3H),                                                         2.40(s, 3H), 3.40(s, 6H), 3.75(t, J=8, 4H), 4.20-4.45(m, 4H), 7.30(s,          2H), 7.50(s, 1H).                                                              .sup.f CI-HRMS: Calcd: 406.1565, Found: 406.1578(M+H); NMR(CDCl.sub.3,         300 MHz): 0.90(t, J=8, 3H),                                                    1.00(t, J=8, 3H), 1.28-1.45(m, 4H), 1.50-1.80(m, 4H), 2.35(s, 3H),             2.50(s, 3H),                                                                   4.20-4.35(m, 1H), 6.10-6.23(m, 1H), 7.30(s, 2H), 7.50(s, 1H).                  .sup.g CI-HRMS: Calcd: 394.1201, Found: 394.1209(M+H); NMR(CDCl.sub.3,         300 MHz): 1.02(t, J=8, 3H),                                                    1.65-1.90(m, 2H), 2.35(s, 3H), 2.48(s, 3H), 3.40(s, 3H), 3.50-3.60(m,          2H), 4.35-4.45(brs, 1H),                                                       6.50-6.60(m, 1H), 7.30(s, 2H), 7.50(s, 1H).                                    .sup.h CI-HRMS: Calcd: 364.1096, Found: 364.1093(M+H); Analysis: Calcd:        C: 56.05; H: 5.27;                                                             N: 19.23; Cl: 19.46; Found: C: 55.96; H: 5.24; N: 18.93; Cl: 19.25;            NMR(CDCl.sub.3, 300 MHz):                                                      1.35(t, J=8, 6H), 2.30(3, 3H), 2.40(s, 3H), 3.95-4.15(m, 4H), 7.30(s,          2H), 7.50(d, J=1, 1H).                                                         .sup.i CI-HRMS: Calcd: 438.1464, Found: 438.1454(M+H); NMR(CDCl.sub.3,         300 MHz): 1.22(t, J=8, 6H),                                                    2.35(s, 3H), 2.47(s, 3H), 3.39(q, J=8, 4H), 3.65(dd, J=8, 1, 2H),              3.73(dd, J=8, 1, 2H), 4.55-                                                    4.65(m, 1H), 6.75(d, J=8, 1H), 7.30(d, J=1, 2H), 7.50(s, 1H).                  .sup.j CI-HRMS: Calcd: 378.1252, Found: 378.1249(M+H); Analysis: Calcd:        C: 57.15; H: 5.61;                                                             N: 18.51; Cl: 18.74; Found: C: 57.56; H: 5.65; N: 18.35; Cl: 18.45;            NMR(CDCl.sub.3, 300 MHz):                                                      1.00(t, J=8, 6H), 1.55-1.70(m, 2H), 1.70-1.85(m, 2H), 2.35(s, 3H), 2.50        (s, 3H),                                                                       4.15-4.25(m, 1H), 6.18(d, J=8, 1H), 7.30(s, 2H), 7.50(s, 1H).                  .sup.k CI-HRMS: Calcd: 398.0939, Found: 398.0922(M+H); Analysis: Calcd:        C: 60.31; H: 4.30;                                                             N: 17.58; Cl: 17.80; Found: C: 60.29; H: 4.59; N: 17.09; Cl: 17.57;            NMR(CDCl.sub.3, 300 MHz):                                                      2.05(s, 3H), 2.50(s, 3H), 3.78(s, 3H), 7.20-7.45(m, 7H), 7.50(d, J=1,          1H).                                                                           .sup.l CI-HRMS: Calcd: 392.1409, Found: 392.1391(M+H); NMR(CDCl.sub.3,         300 MHz):                                                                      0.98(t, J=8, 6H), 1.70-1.85(m, 4H), 2.30(s, 3H), 2.40(s, 3H),                  3.80-4.10(m, 4H),                                                              7.30(s, 2H), 7.50(d, J=1, 1H).                                                 .sup.m CI-HRMS: Calcd: 392.1409, Found: 392.1415(M+H); Analysis: Calcd:        C: 58.17; H: 5.92;                                                             N: 17.85; Cl: 18.07; Found: C: 58.41; H: 5.85: N: 18.10; Cl: 17.75;            NMR(CDCl.sub.3, 300 MHz):                                                      0.90-1.05(m, 6H), 1.35-1.55(m, 2H), 1.55-1.85(m, 4H), 2.35(s, 3H),             2.48(s, 3H),                                                                   4.20-4.35(m, 1H), 6.15(d, J=8, 1H), 7.30(s, 2H), 7.50(d, J=1, 1H).             .sup.n CI-HRMS: Calcd: 337.0623, Found: 337.0689(M+H); Analysis: Calcd:        C: 53.43; H: 4.18;                                                             N: 16.62; Cl: 21.03, Found: C: 53.56; H: 4.33; N: 16.56; Cl: 20.75;            NMR(CDCl.sub.3, 300 MHz):                                                      1.60(t, J=8, 3H), 2.40(s, 3H), 2.55(s, 3H), 4.80(q, J=8, 2H), 7.30(d, J        =8, 1H),                                                                       7.35(dd, J=8, 1, 1H), 7.55(d, J=1H).                                           .sup.o CI-HRMS: Calcd: 383.2321, Found: 383.2309(M+H); NMR(CDCl.sub.3,         300 MHz): 2.00(s, 6H),                                                         2.20(s, 3H), 2.30(s, 3H), 2.45(s, 3H), 3.45(s, 6H), 3.61(dd, J=8, 8, 2H),      3.70(dd, J=8, 8, 2H),                                                          4.60-4.70(m, 1H), 6.70(d, J=8, 1H), 6.94(s, 2H).                               .sup.p CI-HRMS: Calcd: 370.2243, Found: 370.2246(M+H); Analysis: Calcd:        C: 65.02; H: 7.38;                                                             N: 18.96; Found: C: 65.22; H: 7.39; N: 18.71; NMR(CDCl.sub.3, 300 MHz):        2.18(s, 3H), 2.30(s, 3H),                                                      2.45(s, 3H), 3.45(s, 6H), 3.60(dd, J=8, 8, 2H), 3.69(dd, J=8, 8, 2H),          4.60-4.70(m, 1H),                                                              6.70(d, J=8, 1H), 7.05(d, J=8, 1H), 7.07(d, J=8, 1H), 7.10(s, 1H).             .sup.q CI-HRMS: Calcd: 384.2400, Found: 384.2393(M+H); NMR(CDCl.sub.3,         300 MHz): 2.16(s, 3H),                                                         2.25(s, 3H), 2.35(s, 3H), 2.39(s, 3H), 3.40(s, 6H), 3.77(t, J=8, 4H),          4.20-4.45(m, 4H),                                                              7.02(d, J=8, 1H) 7.05(s, 1H), 7.10(d, J=7, 1H).                                .sup.r CI-HRMS: Calcd: 354.2294, Found: 354.2271(M+H); Analysis: Calcd:        C: 67.96; H: 7.71;                                                             N: 19.81; Found: C: 67.56; H: 7.37; N: 19.60; NMR(CDCl.sub.3, 300 MHz):        1.03(t, J=8, 3H),                                                              1.65-1.88(m, 2H), 2.17(s, 3H), 2.30(s, 3H), 2.35(s, 3H), 2.45(s, 3H),          3.40(s, 3H), 3.50-                                                             3.62(m, 2H), 4.30-4.45(m, 1H), 6.51(d, J=8, 1H), 7.04(d, J=8, 1H),             7.10(d, J=8, 1H), 7.12(s, 1H).                                                 .sup.s CI-HRMS: Calcd: 338.2345, Found: 338.2332(M+H); Analysis: Calcd:        C: 71.18; H: 8.06;                                                             N: 20.75; Found: C: 71.43; H: 7.80; N: 20.70; NMR(CDCl.sub.3, 300 MHz):        1.00(t, J=8, 6H),                                                              1.55-1.70(m, 2H), 1.70-1.85(m, 2H), 2.19(s, 3H), 2.30(s, 3H), 2.35(s,          3H), 2.46(s, 3H),                                                              4.15-4.26(m, 1H), 6.17(d, J=8, 1H), 7.06(d, J=8, 1H), 7.10(d, J=1, 1H),        7.13(s, 1H).                                                                   .sup.t CI-HRMS: Calcd: 324.2188, Found: 324.2188(M+H); NMR(CDCl.sub.3,         300 MHz): 1.25(t,                                                              J=8, 6H), 2.16(s, 3H), 2.28(s, 3H), 2.35(s, 3H), 2.40(s, 3H),                  3.95-4.20(m, 4H), 7.05(dd,                                                     J=8, 1, 1H), 7.07(s, 1H), 7.10(d, J=1, 1H).                                    .sup.u CI-HRMS: Calcd: 346.1780, Found: 346.1785(M+H); Analysis: Calcd:        C: 66.07; H: 5.54;                                                             N: 28.39; Found: C: 66.07; H: 5.60; N: 27.81; NMR(CDCl.sub.3, 300 MHz):        2.15(s, 3H), 2.32(s, 3H)                                                       2.17(s, 3H), 2.52(s, 3H), 5.25-5.35(m, 4H), 7.08(s, 2H), 7.15(s, 1H).          .sup.v CI-HRMS: Calcd: 340.2137, Found: 340.2137(M+H); Analysis: Calcd:        C: 67.23; H: 7.42;                                                             N: 20.63; Found:C: 67.11; H: 7.39; N: 20.26; NMR(CDCl.sub.3, 300 MHz):         1.40(d, J=8, 3H),                                                              2.16(s, 3H), 2.32(s, 3H), 2.35(s, 3H), 2.47(s, 3H), 3.42(s, 3H),               3.50-3.60(m, 2H), 4.50-                                                        4.15(m, 1H), 6.56(d, J=8, 1H), 7.00-7.15(m, 3H).                               .sup.w CI-HRMS: Calcd: 355.2134, Found: 355.2134(M+H); NMR(CDCl.sub.3,         300 MHz): 1.05(t, J=8, 3H),                                                    1.85-2.00(m, 2H), 2.17(s, 3H), 2.36(s, 6H), 2.50(s, 3H), 3.41(s, 3H),          3.45(dd, J=8, 3, 1H), 3.82                                                     (dd, J=8, 1, 1H), 5.70-5.80(m, 1H), 7.00-7.20 (m, 3H).                         .sup.x CI-HRMS: Calcd: 364.2501, Found: 364.2501(M+H); NMR(CDCl.sub.3,         300 MHz): 0.35-0.43                                                            (m, 2H), 0.50-0.60(m, 2H), 0.98(t, J=8, 3H), 1.20-1.30(m, 1H),                 1.72-1.90(m, 2H), 2.18(s, 3H)                                                  2.28(s, 3H), 2.35(s, 3H), 2.40(s, 3H), 3.88-4.03(m, 2H), 4.03-4.20(m,          2H), 7.00-7.15(m, 3H).                                                         .sup.y CI-HRMS: Calcd: 353.2454, Found: 353.2454(M+H); Analysis: Calcd:        C: 68.15; H: 8.02; N:                                                          23.84; Found: C: 67.43; H: 7.81; N: 23.45; NMR(CDCl.sub.3, 300 MHz):           1.38(d, J=8, 3H), 2.18(s,                                                      3H), 2.30-2.40(m, 12H), 2.47 93, 3H), 2.60-2.75(m, 2H), 4.30-4.50(m, 1H),      6.60-6.70(m, 1H),                                                              7.00-7.15(m, 3H).                                                              .sup.z CI-HRMS: Calcd: 361.2140, Found: 361.2128(M+H); NMR(CDCl.sub.3,         300 MHz): 0.75-0.83(m,                                                         2H), 1.00-1.10(m, 2H), 2.17(s, 3H), 2.30(s, 3H), 2.36(s, 3H), 2.47(s,          3H), 2.85(t, J=8, 2H),                                                         3.30-3.40(m, 1H), 4.40-4.55(m, 2H), 7.00-7.18(m, 3H).                          .sup.aa CI-HRMS: Calcd: 363.2297, Found: 363.2311(M+H); NMR(CDCl.sub.3,        300 MHz): 1.01(t, 3H,                                                          J=8), 1.75-1.90(m, 2H), 2.15(s, 3H), 2.19(s, 3H), 2.35(s, 3H), 2.40(s,         3H), 2.40(s, 3H), 2.98(t,                                                      2H, J=8), 3.97-4.15(m, 2H), 4.15-4.30(m, 2H), 7.03(d, 1H, 1H), 7.08(d,         1H, J=8), 7.10(s, 1H).                                                         .sup.ab CI-HRMS: Calcd: 363.2297, Found: 363.2295(M+H); NMR(CDCl.sub.3,        300 MHz): 1.01(t, 3H,                                                          J=8), 1.35-1.55(m, 2H), 1.75-1.90(m, 2H), 2.15(s, 3H), 2.30(s, 3H),            2.36(s, 3H), 2.46(s, 3H),                                                      4.10-4.30(m, 2H), 4.95-5.10(br s, 2H), 7.05(d, 1H, J=8), 7.10(d, 1H,           J=8), 7.15(s, 1H).                                                             .sup.ac CI-HRMS: Calcd: 368.2450, Found: 368.2436; Analysis: Calcd: C,         68.62, H, 7.95, N, 19.06;                                                      Found: C, 68.73, H, 7.97, N, 19.09; NMR(CDCl.sub.3, 300 MHz): 1.05(t,          J=8, 3H), 1.70-1.90(m, 2H),                                                    2.01(d, J=3, 6H), 2.20(s, 3H), 2.30(s, 3H), 2.46, 2.465(s, s, 3H), 3.42,       3.48(s, s, 3H), 3.53-3.63                                                      (m, 2H), 4.35-4.45(m, 1H), 6.73(d, J=8, 1H), 6.97(s, 2H).                      .sup.ad CI-HRMS: Calcd: 352.2501, Found: 352.2500(M+H): Analysis: Calcd:       C: 71.76; H: 8.33;                                                             N: 19.92, Found: C: 71.55; H: 8.15; N: 19.28; NMR(CDCl.sub.3, 300 MHz):        1.01(t, J=8, 6H), 1.58-                                                        1.70(m, 2H), 1.70-1.85(m, 2H), 2.02(s, 6H), 2.19(s, 3H), 2.45(s, 3H),          4.12-4.28(m, 1H), 6.18(d,                                                      J=8, 1H), 6.95(s, 2H).                                                         .sup.ae CI-HRMS: Calcd: 398.2556, Found: 398.2551(M+H); Analysis: Calcd:       C: 66.47; H: 7.86;                                                             N: 17.62, Found: C: 66.74; H: 7.79; N: 17.70; NMR(CDCl.sub.3, 300 MHz):        2.00(s, 6H), 2.12(s, 3H),                                                      2.30(s, 3H), 2.37(s, 3H), 3.40(s, 6H), 3.78(t, J=8, 4H), 4.25-4.40(m,          4H), 6.93(s, 2H).                                                              .sup.af CI-HRMS: Calcd: 450.1141, Found: 450.1133(M+H); Analysis: Calcd:       C: 50.67; H: 5.37;                                                             N: 15.55; Br: 17.74; Found: C: 52.36; H: 5.84; N: 14.90; Br: 17.44;            NMR(CDCl.sub.3, 300 MHz):                                                      2.32(s, 3H), 2.57(s, 3H), 3.42(s, 6H), 3.60(q, J=8, 2H), 3.69(q, J=8,          2H), 3.82(s, 3H),                                                              4.60-4.70(m, 1H), 6.73(d, J=8, 1H), 6.93(dd, J=8, 1, 1H), 7.22(d, J=8,         1H).                                                                           .sup.ag CI-HRMS: Calcd: 434.1192, Found: 434.1169(M+H); Analysis: Calcd:       C: 52.54; H: 5.58;                                                             N: 16.12; Br: 18.40; Found: C: 52.57; H: 5.60; N: 15.98; Br: 18.22;            NMR(CDCl.sub.3, 300 MHz):                                                      1.00-1.07(m, 3H), 1.65-1.85(m, 2H), 2.35(s, 3H), 2.46, 2.47(s, s, 3H),         3.40, 3.45(s, s, 3H),                                                          3.83(s, 3H), 4.35-4.45(m, 1H), 6.55(d, J=8, 1H), 6.92(dd, J=8, 1, 1H),         7.20-7.30(m, 2H).                                                              .sup.ah CI-HRMS: Calcd: 337.2266, Found: 337.2251(M+H); Analysis: Calcd:       C: 70.18; H: 8.06;                                                             N: 20.75; Found: C: 70.69; H: 7.66; N: 20.34; NMR(CDCl.sub.3, 300 MHz):        1.35(t, J=8, 6H), 2.01(s,                                                      6H), 2.15(s, 3H), 2.30(s, 3H), 2.38(s, 3H), 4.07(q, J=8, 4H), 6.93(s,          2H).                                                                           .sup.ai CI-HRMS: Calcd: 412.2713, Found: 412.2687(M+H); Analysis: Calcd:       C: 67.13; H: 8.08;                                                             N: 17.02; Found: C: 67.22; H: 7.85; N: 17.13; NMR(CDCl.sub.3, 300 MHz):        1.24(t, J=8, 6H), 2.00(s,                                                      6H), 2.20(s, 3H), 2.30(s, 3H), 2.43(s, 3H), 3.60(q, J=8, 4H), 3.66(dd,         J=8, 3, 2H), 3.75(dd, J=8,                                                     3, 2H), 4.55-4.65(m, 1H), 6.75(d, J=8, 1H), 6.95(s, 2H).                       .sup.aj CI-HRMS: Calcd: 398.2556, Found: 398.2545(M+H); Analysis: Calcd:       C: 66.47; H: 7.86;                                                             N: 17.62; Found: C: 66.87; H: 7.62; N: 17.75; NMR(CDCl.sub.3, 300 MHz):        1.95-2.10(m, 8H), 2.20(s,                                                      3H), 2.32(s, 3H), 2.44(s, 3H), 3.38(s, 3H), 3.42(s, 3H), 3.50-3.70(m,          4H), 4.58-4.70(m, 1H), 6.87                                                    (d, J=8, 1H), 6.95(s, 2H).                                                     .sup.ak CI-HRMS: Calcd: 338.1981, Found: 338.1971(M+H); Analysis: Calcd:       C: 67.63; H: 6.87;                                                             N: 20.06; Found: C: 67.67; H: 6.82; N: 20.31; NMR(CDCl.sub.3, 300 MHz):        2.15(s, 3H), 2.29(s, 3H),                                                      2.35(s, 3H), 2.43(s, 3H), 3.90(t, J=8, 4H), 4.35-4.45(m, 4H),                  7.00-7.15(m, 3H).                                                              .sup.al CI-HRMS: Calcd: 464.1297, Found: 464.1297(M+H); NMR(CDCl.sub.3,        300 MHz): 2.28(s, 3H),                                                         2.40(s, 3H), 3.40(s, 6H), 3.75(t, J=8, 4H), 3.83(s, 3H), 4.20-4.50(m,          4H), 6.93(dd, J=8, 1,                                                          1H), 7.20(s, 1H), 7.24(d, J=1, 1H).                                            .sup.am CI-HRMS: Calcd: 418.1242, Found: 418.1223(M+H); NMR(CDCl.sub.3,        300 MHz): 1.00(t, d,                                                           J=8, 1, 6H), 1.55-1.75(m, 4H), 2.34(s, 3H), 2.49(s, 3H), 2.84(s, 3H),          4.15-4.27(m, 1H), 6.19(d,                                                      J=8, 1H), 6.93(dd, J=8, 1, 1H), 7.21-7.30(m, 2H).                              .sup.an CI-HRMS: Calcd: 404.1086, Found: 404.1079(M+H); NMR(CDCl.sub.3,        300 MHz): 1.35(t,                                                              J=8, 6H), 2.28(s, 3H), 2.40(s, 3H), 3.83(s, 3H), 3.90-4.08(m, 2H),             4.08-4.20(m, 2H),                                                              6.92(dd, J=8, 1, 1H), 7.20-7.25(m, 2H).                                        .sup.ao CI-HRMS: Calcd: 308.1875, Found: 308.1872(M+H); NMR(CDCl.sub.3,        300 MHz): 0.75-0.80(m,                                                         2H), 0.93-1.00(m, 2H), 2.16(s, 3H), 2.28(s, 3H), 2.35(s, 3H), 2.53(s,          3H), 3.00-3.10(m, 1H),                                                         6.50-6.55(m, 1H), 7.00-7.15(m, 3H).                                            .sup.ap CI-HRMS: Calcd: 397.1988, Found: 397.1984(M+H); NMR(CDCl.sub.3,        300 MHz): 2.43(s, 3H),                                                         2.50(s, 3H), 3.43(s, 3H), 3.61(dd, J=8, 8, 2H), 3.69(dd, J=8, 8, 2H),          3.88(s, 3H), 4.58-4.70(m,                                                      1H), 6.75(d, J=8, 1H), 7.20(dd, J=8, 1, 1H), 7.25(d, J=1, 1H), 7.40(s,         1H).                                                                           .sup.aq CI-HRMS: Calcd: 375.2297, Found: 375.2286(M+H); Analysis: Calcd:       C: 70.56; H: 7.01; N:                                                          22.44; Found: C: 70.49; H: 6.99; N: 22.45; NMR(CDCl.sub.3, 300 MHz):           0.79-0.85(m, 2H), 1.00-1.05                                                    (m, 1H), 2.00(s, 6H), 2.19(s, 3H), 2.32(s, 3H), 2.44(s, 3H), 2.84(t, J=8,      2H), 3.30-3.40(m, 1H),                                                         4.50(t, J=8, 2H), 6.95(s, 2H).                                                 .sup.ar CI-HRMS: Calcd: 434.1192, Found: 434.1189(M+H); Analysis: Calcd:       C: 52.54; H: 5.58;                                                             N: 16.12; Br: 18.40; Found: C: 52.75; H: 5.59; N: 16.09; Br: 18.67;            NMR(CDCl.sub.3, 300 MHz):                                                      2.19(s, 3H), 2.30(s, 3H), 2.47(s, 3H), 3.43(s, 6H), 3.60(dd, J=8, 8, 2H),      3.70(dd, J=8,8, 2H),                                                           4.58-4.70(m, 1H), 6.71(d, J=8, 1H), 7.08(d, J=8, 1H), 7.37(d, J=8, 1,          1H), 7.45(d, J=1, 1H).                                                         .sup.as CI-HRMS: Calcd: 448.1348, Found: 448.1332(M+H); Analysis: Calcd:       C: 53.58; H: 5.85;                                                             N: 16.62; Br: 17.82; Found: C: 53.68; H: 5.74; N: 15.52; Br: 13.03;            NMR(CDCl.sub.3, 300 MHz):                                                      1.95-2.10(m, 2H), 2.20(s, 3H), 2.30(s, 3H), 2.47(s, 3H), 3.38(s, 3H),          3.41(s, 3H), 3.50-3.67(m,                                                      4H), 4.55-4.70(m, 1H), 6.89(d, J=8, 1H), 7.05(d, J=8, 1H), 7.35(dd, J=8,       1, 1H), 7.47(d,                                                                J=1, 1H).                                                                      .sup.at CI-HRMS: Calcd: 400.2349, Found: 400.2348(M+H); Analysis: Calcd:       C: C: 63.14; H: 7.32;                                                          N: 17.53; Found: C:63.40; H: 7.08; N: 17.14; NMR(CDCl.sub.3, 300 MHz):         2.16(s, 3H), 2.20(s, 3H),                                                      2.30(s, 3H), 2.46(s, 3H), 3.42(s, 6H), 3.60(q, J=8, 2H), 3.70(q, J=8,          2H), 3.85(s, 3H),                                                              4.59-4.70(m, 1H), 6.70(d, J=8, IH), 6.76(s, 1H), 6.96(s, 1H).                  .sup.au CI-HRMS: Calcd: 414.2505, Found: 414.2493(M+H); NMR(CDCl.sub.3,        300 MHz): 2.15(s, 3H),                                                         2.19(s, 3H), 2.25(s, 3H), 2.40(s, 3H), 3.40(s, 6H), 3.76(t, J=8, 4H),          3.84(s, 3H), 4.20-4.45(m,                                                      4H), 6.77(s, 1H), 6.93(s, 1H).                                                 .sup.av CI-HRMS: Calcd: 368.2450, Found: 368.2447(M+H); NMR(CDCl.sub.3,        300 MHz): 1.00(t,                                                              J=8, 6H), 1.55-1.85(m, 4H), 2.19(s, 3H), 2.20(s, 3H), 2.30(s, 3H),             2.47(s, 3H), 3.88(s, 3H),                                                      4.10-4.30(m, 1H), 6.15(d, J=8, 1H), 6.78(s, 1H), 6.98(s, 1H).                  .sup.aw CI-HRMS: Calcd: 353.2216, Found: 353.2197(M+H); NMR(CDCl.sub.3,        300 MHz): 1.35(t, J=8,                                                         6H), 2.17(s, 3H), 2.19(s, 3H), 2.28(s, 3H), 2.40(s, 3H), 3.85(s, 3H),          3.90-4.20(m, 4H), 6.78                                                         (s, 1H), 6.95(s, 1H).                                                          .sup.ax CI-HRMS: Calcd: 390.1697, Found: 390.1688(M+H); Analysis: Calcd:       C: 58.53; H: 6.20; N:                                                          17.96; Cl: 9.09; Found: C: 58.95; H: 6.28; N: 17.73; Cl: 9.15;                 NMR(CDCl.sub.3, 300 MHz): 2.35(s,                                              3H), 2.37(s, 3H), 2.48(s, 3H), 3.42(s, 6H), 3.60(dd, J=8, 8, 2H)3.68(dd,       J=8, 8, 2H), 4.59-4.72                                                         (m, 1H), 6.72(d, J=8, 1H), 7.12(d, J=8, 1H), 7.23(d, J=8, 1H), 7.32(s,         1H).                                                                           .sup.ay CI-HRMS: Calcd: 374.1748, Found: 374.1735(M+H); Analysis: Calcd:       C: 61.04; H: 6.47;                                                             N: 18.73; Cl: 9.48; Found: C: 61.47; H: 6.54; N: 18.23; Cl: 9.61;              NMR(CDCl.sub.3, 300 MHz):                                                      1.01(t, J=8, 3H), 1.62-1.88(m, 4H), 2.35(s, 3H), 2.37(s, 3H), 2.48(d,          J=1, 3H), 3.40,                                                                3.45(s, s, 3H), 3.50-3.64(m, 2H), 4.38-4.47(m, 1H), 6.53(d, J=8, 1H),          7.12(d, J=8, 1H),                                                              7.07(d, J=8, 1H), 7.12(s, 1H).                                                 .sup.az CI-HRMS: Calcd: 404.1853, Found: 404.1839(M+H); NMR(CDCl.sub.3,        300 MHz): 2.29(s, 3H),                                                         2.38(s, 3H), 2.40(s, 3H), 3.40(s, 6H), 3.76(t, J=8, 4H), 4.20-4.45(m,          4H), 7.11(d, J=8, 1H),                                                         7.22(d, J=8, 1H), 7.31(s, 1H).                                                 .sup.ba CI-HRMS: Calcd: 404.1853, Found: 404.1859(M+H); Analysis: C:           59.47; H: 6.50; N: 17.34;                                                      Cl: 8.79; Found: C: 59.73; H: 6.46; N: 17.10; Cl: 8.73; NMR(CDCl.sub.3,        300 MHz): 1.95-2.08(m,                                                         2H), 2.35(s, 3H), 2.38(s, 3H), 2.46(s, 3H), 3.38(s, 3H), 3.41(s, 3H),          3.50-3.65(m, 4H), 4.56-                                                        4.70(m, 1H), 6.85(d, J=8, 1H), 7.12(d, J=8, 1H), 7.45(d, J=8, 1H),             7.32(s, 1H).                                                                   .sup.bb CI-HRMS: Calcd: 391.2246, Found: 391.2258(M+H); Analysis: C:           67.67; H: 6.71; N: 21.52;                                                      Found: C: 67.93; H: 6.70; N: 21.48; NMR(CDCl.sub.3, 300 MHz):                  0.76-0.84(m, 2H), 0.84-0.91                                                    (m, 2H), 1.00-1.08(m, 2H), 2.15(s, 3H), 2.20(s, 3H), 2.29(s, 3H), 2.45(s,      3H), 2.85(t, J=8,                                                              2H), 3.28-3.30(m, 1H), 3.85(s, 3H), 6.78(s, 1H), 6.95(s, 1H).                  .sup.bc CI-HRMS: Calcd: 386.2192, Found: 386.2181(M+H); Analysis: C:           62.32; H: 7.06; N: 18.17;                                                      Found: C: 62.48; H: 6.83; N: 18.15; NMR(CDCl.sub.3, 300 MHz): 7.1(d, 1H,       J=8), 6.9(d, 1H, J=1),                                                         6.8(dd, 1H, J=8,1), 6.7(br.d, 1H, J=8), 4.7-4.6(m, 1H), 3.85(s, 3H),           3.70-3.55(m, 4H),                                                              3.45(s, 6H), 2.5(s, 3H), 2.3(s, 3H), 2.15(s, 3H).                              .sup.bd CI-HRMS: Calcd: 400.2349, Found: 400.2336(M+H); NMR(CDCl.sub.3,        300 MHz): 7.1(d, 1H, J=7),                                                     6.85(d, 1H, J=1), 6.75(dd, 1H, J=7, 1), 4.45-4.25(br.s, 4H), 3.75(t, 4H,       J=7), 3.4(s, 6H), 2.4                                                          (s, 3H), 2.25(s, 3H), 2.15(s, 3H).                                             .sup.be CI-HRMS: Calcd: 370.2243, Found: 370.2247(M+H); Analysis: C:           65.02; H: 7.38; N: 18.96;                                                      Found: C: 65.28; H: 7.27; N: 18.71; NMR(CDCl.sub.3, 300 MHz): 7.1(d, 1H,       J=8), 6.85(d, 1H, J=1),                                                        6.8(dd, 1H, J=8, 1), 6.5(br. d, 1H, J=1), 4.5-4.3(m, 1H), 3.85(s, 3H),         3.65-3.5(m, 2H), 3.4(s, 2H),                                                   2.5(s, 3H), 2.3(s, 3H), 2.2(s, 3H), 1.9-1.7(m, 2H), 1.05(t, 3H, J=7).          .sup.bf CI-HRMS: Calcd: 379.2246, Found: 379.2248(M+H); NMR(CDCl.sub.3,        300 MHz): 7.1(d, 1H, J=8),                                                     6.85(d, 1H, J=1), 6.8(dd, 1H, J=8, 1), 4.3-4.0(m, 4H), 3.85(s, 3H),            3.0(t, 2H, J=7), 2.45(s, 3H),                                                  2.3(s, 3H), 2.2(s, 3H), 1.9-1.8(m, 2H), 1.0(t, 3H, J=7).                       .sup.bg CI-HRMS: Calcd: 340.2137, Found: 340.2122(M+H); NMR(CDCl.sub.3,        300 MHz): 7.1(d, 1H, J=8),                                                     6.85(d, 1H, J=1), 6.75(dd, 1H, J=8,1), 4.2-4.0(br.m, 4H), 3.85(s, 3H,          2.4(s, 3H), 2.3( s, 3H), 2.2                                                   (s, 3H), 1.35(t, 6H, J=7).                                                     .sup.bh CI-HRMS: Calcd: 313.1665, Found: 313.6664(M+H).                        .sup.bi CI-HRMS: Calcd: 400.2349, Found: 400.2346(M+H); NMR(CDCl.sub.3,        300 MHz): 7.1(d, 1H, J=7),                                                     6.9-6.75(m, 3H), 4.7-4.55(m, 1H), 3.8(s, 3H), 3,7-3.5(m, 4H), 3.45(s,          3H), 3.35(s, 3H),                                                              2.5(s, 3H), 2.3(s, 3H), 2.2(s, 3H), 2.1-1.95(m, 2H).                           .sup.bj CI-HRMS: Calcd: 377.2090, Found: 377.2092(M+H); Analysis: C:           67.00; H: 6.44; N: 22.32;                                                      Found: C: 67.35; H: 6.44; N: 22.23; NMR(CDCl.sub.3, 300 MHz): 7.1(d, 1H,       J=8), 6.9(d, 1H, J=1),                                                         6.8(dd, 1H, J=8,1), 4.55-4.4(m, 2H), 3.85(s, 3H), 3.4-3.3(m, 1H), 2.85(t,      2H, J=7), 2.5(s, 3H),                                                          2.3(s, 3H), 2.2(s, 3H), 1.1-1.0(m, 2H), 0.85-0.75(m, 2H).                      .sup.bk CI-HRMS: Calcd: 413.2427, Found: 413.2416(M+H); NMR(CDCl.sub.3,        300 Hz): 7.1(d, 1H, J=8),                                                      6.85(d, 1H, J=1), 6.75(dd, 1H, J=8, 1), 4.6(m, 1H), 3.85(s, 3H),               3.75-3.6(m, 4H), 3.6(q, 4H,                                                    J=7), 2.5(s, 3H), 2.3 s, 3H), 2.2(s, 3H), 1.25(t, 6H, J=7).                    .sup.bl CI-HRMS: Calcd: 420.1802, Found: 420.1825(M+H);                        .sup.bm CI-HRMS: Calcd: 390.1697, Found: 390.1707(M+H);                        .sup.bn CI-HRMS: Calcd: 397.1465, Found: 397.1462(M+H);                        .sup.bo CI-HRMS: Calcd: 360.1513, Found: 360.1514(M+H);                        .sup.bp CI-HRMS: Calcd: 374.1748, Found: 374.1737(M+H);                        .sup.bq CI-HRMS: Calcd: 479.1155, Found: 479.1154(M+H);                        .sup.br CI-HRMS: Calcd: 463.1219, Found: 463.1211(M+H); Analysis Calcd:        C: 51.96, H: 5.23,                                                             N, 15.15, Br: 17.28; Found: C: 52.29, H: 5.62, N: 14.79, Br: 17.47             .sup.bs CI-HRMS: Calcd: 433.1113, Found: 433.1114(M, .sup.79 Br);              .sup.bt NH.sub.3 -CI MS: Calcd: 406, Found: 406(M+H)+; NMR(CDCl.sub.3,         300 MHz): δ 7.28(d, J=10 Hz,                                             1H), 7.03(d, J=8 Hz, 1H), 6.96(s, 1H), 6.7(d, J=9, 1H), 4.63(m, 1H),           3.79(s, 3H), 3.6(m, 4H),                                                       3.42(s, 6H), 2.47(s, 3H), 2.32(s, 3H).                                         __________________________________________________________________________

Example 431 Preparation of 2,4,7-dimethyl-8-(4-methoxy-2-methylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Formula 1, where R³ is CH₃, R¹ is CH₃, Z is C--CH₃, Ar is 2,4-dimethylphenyl)

5-Acetamidino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole, acetic acid salt (602 mg, 2 mmol) was mixed with a saturated NaHCO₃ solution (10 mL). The aqueous mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo. The residue was taken up in toluene (10 mL) and trimethyl orthoacetate 0.36 g, 3 mmol) was added to the suspension. The reaction mixture was heated to reflux temperature under a nitrogen atmosphere and stirred for 16 hours. After being cooled to ambient temperature, the reaction mixture was concentrated in vacuo to give an oily solid. Column chromatography (CHCl₃ :MeOH::9:1) afforded, after removal of solvent in vacuo, a yellow viscous oil (Rf=0.6, 210 mg, 37% yield): NMR (CDCl₃, 300 MHz): 7.15 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.85 (dd, 1H, J=8,1), 3.85 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H); CI-HRMS: Calcd: 283.1559, Found: 283.1554 (M+H).

Example 432 7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is OH, Z is C--Me, Ar is 2-chloro-4-methylphenyl)

5-Amino-4-(2-chloro-4-methylphenyl)-3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 mL) with stirring. Ethyl acetoacetate (1.18 mL, 9.2 mmol) was then added dropwise to the resulting solution. The reaction mixture was then heated to reflux temperature and stirred for 16 hours, then cooled to room temperature. Ether (100 mL) was added and the resulting precipitate was collected by filtration. Drying in vacuo afforded a white solid 1.0 g, 42% yield): NMR (CDCl₃, 300 Hz): 8.70 (br.s 1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H), 5.62 (s, 1H), 2.35 (s, 6H), 2.29 (s, 3H); CI-MS: 288 (M+H).

Example 433 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is Cl, Z is C--Me, Ar is 2-chloro-4-methylphenyl)

A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 mmol), N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) was stirred at reflux temperature for 3 hours, then it was cooled to ambient temperature. The volatiles were removed in vacuo. Flash chromatography (EtOAc:hexane::1:2) on the residue gave 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (900 mg, 84% yield) as a yellow oil: NMR (CDCl₃, 300 Hz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 71.6 (d, 1H, J=7), 6.80 (s, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS: 306 (M+H).

Example 434 7-(pentyl-3-amino)-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is pentyl-3-amino, Z is C--Me, Ar is 2-chloro-4-methylphenyl)

A solution of 3-pentylamine (394mg, 6.5 mmol) and 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (200 mg, 0.65 mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at 150° C. for 2 hours; then it was cooled to ambient temperature. The reaction mixture was then poured onto water (100 mL) and mixed. Three extractions with dichloromethane, washing the combined organic layers with brine, drying over MgSO₄, filtration and removal of solvent in vacuo produced a yellow solid. Flash chromatography (EtOAc:hexanes::1:4) afforded a white solid (140 mg, 60% yield): mp 139-141° C.; NMR (CDCl₃, 300 Hz):7.32 (s, 1H), 7.27 (d, 1H, J=8), 7.12 (d, 1H, J=7), 6.02 (d, 1H, J=9), 5.78 (s, 1H), 3.50-3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H), 1.82-1.60 (m, 4H), 1.01 (t, 6H, J=8); Analysis Calcd for C₂₀ H₂₅ ClN₄ : C, 67.31; H, 7.06; N, 15.70; Cl, 9.93; Found: C, 67.32; H, 6.95; N, 15.50; Cl, 9.93.

The examples delineated in TABLE 2 may be prepared by the methods outlined in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example, EtOAc is ethyl acetate.

                                      TABLE 2                                      __________________________________________________________________________      ##STR38##                                                                     Ex. Z    R.sub.3       Ar        mp (° C.)                              __________________________________________________________________________     435.sup.b                                                                          C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2,4-Cl.sub.2 --Ph                                                                        71-73                                         436.sup.c                                                                          C--Me                                                                               N(Bu)Et       2,4-Cl.sub.2 --Ph                                                                        86-87                                         437.sup.d                                                                          C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2,4-Cl.sub.2 --Ph                                                                        110-111                                       438.sup.e                                                                          C--Me                                                                               N(Pr)CH.sub.2 CH.sub.2 CN                                                                    2,4-Cl.sub.2 --Ph                                                                        83-85                                         439.sup.f                                                                          C--Me                                                                               NH-3-pentyl   2,4-Cl.sub.2 --Ph                                                                        175-176                                       440.sup.g                                                                          C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2,4-Cl.sub.2 --Ph                                                                        107                                           441.sup.h                                                                          C--Me                                                                               NHCH(Et).sub.2                                                                               2,4-Me.sub.2 --Ph                                                                        oil                                           442.sup.i                                                                          C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2,4-Me.sub.2 --Ph                                                                        103-105                                       443.sup.j                                                                          C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2,4-Me.sub.2 --Ph                                                                        87-89                                         444.sup.k                                                                          C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2,4-Me.sub.2 --Ph                                                                        133(dec)                                      445.sup.l                                                                          C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Cl,4-MePh                                                                              77-78                                         446.sup.m                                                                          C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Cl,4-MePh                                                                              131-133                                       447.sup.n                                                                          C--Me                                                                               NHCH(Et).sub.2                                                                               2-Cl,4-MePh                                                                              139-141                                       448.sup.o                                                                          C--Me                                                                               NEt.sub.2     2,4-Me.sub.2 --Ph                                                                        92-94                                         449.sup.p                                                                          C--Me                                                                               N(Pr)CH.sub.2 CH.sub.2 CN                                                                    2,4-Me.sub.2 --Ph                                                                        143-144                                       450.sup.q                                                                          C--Me                                                                               N(Bu)CH.sub.2 CH.sub.2 CN                                                                    2,4-Me.sub.2 --Ph                                                                        115-117                                       451.sup.r                                                                          C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2,4-Me.sub.2 --Ph                                                                        oil                                           452.sup.s                                                                          C--Me                                                                               NHCH(Et).sub.2                                                                               2-Me,4-MeOPh                                                                             104-106                                       453.sup.t                                                                          C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Me,4-MeOPh                                                                             115-116                                       454.sup.u                                                                          C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Me,4-MeOPh                                                                             oil                                           455.sup.v                                                                          C--Me                                                                               (S)--NHCH(CH.sub.2 CH.sub.2 OMe)--                                                           2-Me,4-MeOPh                                                                             oil                                                    (CH.sub.2 OMe)                                                        456.sup.w                                                                          C--Me                                                                               (S)--NHCH(CH.sub.2 CH.sub.2 OMe)--                                                           2,4-Me.sub.2 --Ph                                                                        oil                                                    (CH.sub.2 OMe)                                                        457.sup.x                                                                          C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Me,4-ClPh                                                                              oil                                           458.sup.y                                                                          C--Me                                                                               NHEt          2,4-Me.sub.2 --Ph                                                                        oil                                           459.sup.z                                                                          C--Me                                                                               NHCH(Et).sub.2                                                                               2-Me,4-ClPh                                                                              94-96                                         460.sup.aa                                                                         C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Me,4-ClPh                                                                              113-114                                       461.sup.ab                                                                         C--Me                                                                               N(Ac)Et       2,4-Me.sub.2 --Ph                                                                        oil                                           462.sup.ac                                                                         C--Me                                                                               (S)--NHCH(CH.sub.2 CH.sub.2 OMe)--                                                           2-Me,4-ClPh                                                                              oil                                                    (CH.sub.2 OMe)                                                        463.sup.ad                                                                         C--Me                                                                               N(Pr)CH.sub.2 CH.sub.2 CN                                                                    2-Me,4-MeOPh                                                                             118-119                                       464.sup.ae                                                                         C--Me                                                                               NEt.sub.2     2-Me,4-MeOPh                                                                             97-99                                         465.sup.af                                                                         C--Me                                                                               (S)--NHCH(CH.sub.2 CH.sub.2 OMe)--                                                           2-Cl,4-MePh                                                                              101-103                                                (CH.sub.2 OMe)                                                        466.sup.ag                                                                         C--Me                                                                               NEt.sub.2     2-Cl,4-MePh                                                                              129-130                                       467.sup.ah                                                                         C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Me,4-MeOPh                                                                             177-178                                       468.sup.ai                                                                         C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Cl,4-MePh                                                                              162-163                                       469.sup.aj                                                                         C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Me,4-MeOPh                                                                             oil                                           470.sup.ak                                                                         C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Cl,4-MePh                                                                              111-113                                       471 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Cl-4-MeOPh                                            472 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Cl-4-MeOPh                                            473 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Cl-4-MeOPh                                            474 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Cl-4-MeOPh                                            475 C--Me                                                                               NEt.sub.2     2-Cl-4-MeOPh                                            476 C--Me                                                                               NH-3-pentyl   2-Cl-4-MeOPh                                            477 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Cl-4-MeOPh                                            478 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Cl-4-MeOPh                                            479 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Br-4-MeOPh                                            480 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Br-4-MeOPh                                            481 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Me-4-MeOPh                                            482 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Me-4-MeOPh                                            483 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Cl-4,5-(MeO).sub.2 Ph                                 484 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Cl-4,5-(MeO).sub.2 Ph                                 485 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Cl-4,5-(MeO).sub.2 Ph                                 486 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Cl-4,5-(MeO).sub.2 Ph                                 487 C--Me                                                                               NEt.sub.2     2-Cl-4,5-(MeO).sub.2 Ph                                                                   99-101                                       488 C--Me                                                                               NH-3-pentyl   2-Cl-4,5-(MeO).sub.2 Ph                                                                  169-170                                       489 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Cl-4,5-(MeO).sub.2 Ph                                 490 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Cl-4,5-(MeO).sub.2 Ph                                 491 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Br-4,5-(MeO).sub.2 Ph                                                                  90-93                                         492 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Br-4,5-(MeO).sub.2 Ph                                                                  110                                           493 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Br-4,5-(MeO).sub.2 Ph                                 494 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Br-4,5-(MeO).sub.2 Ph                                 495 C--Me                                                                               NEt.sub.2     2-Br-4,5-(MeO).sub.2 Ph                                 496 C--Me                                                                               NH-3-pentyl   2-Br-4,5-(MeO).sub.2 Ph                                 497 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Br-4,5-(MeO).sub.2 Ph                                 498 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Br-4,5-(MeO).sub.2 Ph                                 499 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Cl-4,6-(MeO).sub.2 Ph                                 500 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Cl-4,6-(MeO).sub.2 Ph                                 501 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Cl-4,6-(MeO).sub.2 Ph                                 502 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Cl-4,6-(MeO).sub.2 Ph                                 503 C--Me                                                                               NEt.sub.2     2-Cl-4,6-(MeO).sub.2 Ph                                 504 C--Me                                                                               NH-3-pentyl   2-Cl-4,6-(MeO).sub.2 Ph                                 505 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Cl-4,6-(MeO).sub.2 Ph                                 506 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Cl-4,6-(MeO).sub.2 Ph                                 507 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-Me-4,6-(MeO).sub.2 Ph                                 508 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-Me-4,6-(MeO).sub.2 Ph                                 509 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-Me-4,6-(MeO).sub.2 Ph                                 510 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Me-4,6-(MeO).sub.2 Ph                                 511 C--Me                                                                               NEt.sub.2     2-Me-4,6-(MeO).sub.2 Ph                                 512 C--Me                                                                               NH-3-pentyl   2-Me-4,6-(MeO).sub.2 Ph                                 513 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Me-4,6-(MeO).sub.2 Ph                                 514 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Me-4,6-(MeO).sub.2 Ph                                 515 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-Br-4,6-(MeO).sub.2 Ph                                 516 C--Me                                                                               NEt.sub.2     2-Br-4,6-(MeO).sub.2 Ph                                 517 C--Me                                                                               NH-3-pentyl   2-Br-4,6-(MeO).sub.2 Ph                                 518 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Br-4,6-(MeO).sub.2 Ph                                 519 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Br-4,6-(MeO).sub.2 Ph                                 520 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-Me-4-MeOPh                                            521 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-Me-4-MeOPh                                            522 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-MeO-4-MePh                                            523 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-MeO-4-MePh                                            524 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-MeO-4-MePh                                            525 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-MeO-4-MePh                                            526 C--Me                                                                               NEt.sub.2     2-MeO-4-MePh                                            527 C--Me                                                                               NH-3-pentyl   2-MeO-4-MePh                                            528 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-MeO-4-MePh                                            529 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-MeO-4-MePh                                            530 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-MeO-4-MePh                                            531 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-MeO-4-MePh                                            532 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-MeO-4-MePh                                            533 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-MeO-4-MePh                                            534 C--Me                                                                               NEt.sub.2     2-MeO-4-MePh                                            535 C--Me                                                                               NH-3-pentyl   2-MeO-4-MePh                                            536 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-MeO-4-MePh                                            537 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-MeO-4-MePh                                            538 C--Me                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                     2-MeO-4-ClPh                                            539 C--Me                                                                               N(CH.sub.2 CH.sub.2 OMe).sub.2                                                               2-MeO-4-ClPh                                            540 C--Me                                                                               NHCH(Et)CH.sub.2 OMe                                                                         2-MeO-4-ClPh                                            541 C--Me                                                                               N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                  2-MeO-4-ClPh                                            542 C--Me                                                                               NEt.sub.2     2-MeO-4-ClPh                                            543 C--Me                                                                               NH-3-pentyl   2-MeO-4-ClPh                                            544 C--Me                                                                               NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                2-MeO-4-ClPh                                            545 C--Me                                                                               NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                2-MeO-4-ClPh                                            __________________________________________________________________________      NOTES FOR TABLE 2:                                                             b) CIHRMS: Calcd: 423.1355; Found: 423.1337 (M + H).                           c) Analysis: Calcd: C, 61.38, H, 6.18, N, 14.32:                               Found: C, 61.54, H, 6.12, N, 14.37.                                            d) Analysis: Calcd: C: 58.02, H, 5.65, N, 14.24;                               Found: C, 58.11, H, 5.52, N, 14.26.                                            e) Analysis: Calcd: C, 59.71, H, 5.26, N, 14.85;                               Found: C, 59.94, H, 5.09, N, 17.23.                                            f) Analysis: Calcd: C, 60.48, H, 5.89, N, 14.85,                               Found: C, 60.62, H, 5.88, N, 14.82.                                            h) CIHRMS: Calcd: 337.2388; Found: 337.2392 (M + H).                           i) Analysis: Calcd: C, 68.45, H, 7.669, N, 15.21,                              Found: C, 68.35, H, 7.49 N, 14.91.                                             j) Analysis: Calcd: C, 69.08, H, 7.915, N, 14.65,                              Found: C, 68.85, H, 7.83, N, 14.54.                                            k) Analysis: Calcd: C, 73.51, H, 7.01, N, 19.48,                               Found: C, 71.57, H, 7.15, N, 19.12.                                            l) CIHRMS: Calcd: 403.1899; Found: 403.1901 (M + H).                           m) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl. 9.13;                     Found: C, 61.90, H, 6.66, N, 13.62, Cl, 9.25.                                  n) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70, Cl. 9.93;                     Found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.                                  o) Analysis: Calcd: C, 74.50, H, 8.14, N, 17.38,                               Found: C, 74.43, H, 7.59, N, 17.16.                                            p) Analysis: Calcd: C, 73.10, H, 7.54, N, 19.37,                               Found: C, 73.18, H, 7.59, N, 18.81.                                            q) Analysis: Calcd: C, 73.57, H, 7.78, N, 18.65,                               Found: C, 73.55, H, 7.79, N, 18.64.                                            r) CIHRMS: Calcd: 353.2333; Found: 353.2341 (M + H).                           s) Analysis: Calcd: C, 71.56, H, 8.02, N, 15.90,                               Found: C, 71.45, H, 7.99, N, 15.88.                                            t) Analysis: Calcd: C, 65.60, H, 7.34, N, 14.57,                               Found: C, 65.42, H, 7.24, N, 14.37.                                            u) CIHRMS: Calcd: 399.2398; Found: 399.2396 (M + H).                           v) CIHRMS: Calcd: 399.2398; Found: 399.2396 (M + H).                           w) CIHRMS: Calcd: 383.2450; Found: 383.2447 (M + H).                           x) CIHRMS: Calcd: 403.1887; Found: 403.1901 (M + H).                           y) CIHRMS: Calcd: 295.1919; Found: 295.1923 (M + H).                           z) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70,                               Found: C, 67.12, H, 6.86, N, 15.53.                                            aa) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl, 9.13;                    Found: C, 62.06, H, 6.37, N, 14.25, Cl, 9.12.                                  ab) CIHRMS: Calcd: 337.2017; Found: 337.2028 (M + H).                          ac) CIHRMS: Calcd: 403.1893; Found: 403.1901 (M + H).                          ad) Analysis: Calcd: C, 70.00, H, 7.22, N, 18.55,                              Found: C, 70.05, H, 7.22, N, 18.36.                                            ae) Analysis: Calcd: C, 70.98, H, 7.74, N, 16.55,                              Found: C, 71.15, H, 7.46, N, 16.56.                                            ag) Analysis: Calcd: C, 66.59, H, 6.76, N, 16.34,                              Found: C, 66.69, H, 6.82, N, 16.20.                                            ah) Analysis: Calcd: C, 70.38, H, 6.71, N, 18.65,                              Found: C, 70.35, H, 6.82, N, 18.83.                                            ai) Analysis: Calcd: C, 66.39, H, 5.85, N, 18.44, Cl, 9.33;                    Found: C, 66.29, H, 5.51, N, 18.36, Cl, 9.31.                                  aj) CIHRMS: calcd: 369.2278; Found: 369.2291 (M + H).                          ak) Analysis: Calcd: C, 64.42, H, 6.77, N, 15.02,                              Found: C, 64.59, H, 6.51, N, 14.81.                                      

The examples delineated in TABLE 3 may be prepared by the methods outlined in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

                                      TABLE 3                                      __________________________________________________________________________      ##STR39##                                                                     Ex.                                                                               Z     R.sub.3          Ar       mp (° C.)                            __________________________________________________________________________     546.sup.a                                                                         C--Me NHCH(Et).sub.2   2-Me-4-Me.sub.2 N--Ph                                                                   164-166                                     547.sup.b                                                                         C--Me S--NHCH(CH.sub.2 CH.sub.2 OMe)--CH.sub.2 OMe                                                    2,4-Me2--Ph                                                                             oil                                         548.sup.c                                                                         C--Me S--NHCH(CH.sub.2 CH.sub.2 OMe)--CH.sub.2 OMe                                                    2-Me-4-Cl--Ph                                                                           oil                                         549.sup.d                                                                         C--Me N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-Me-4-Cl--Ph                                                                           115-116                                     550.sup.e                                                                         C--Me NHCH(Et)CH.sub.2 CN                                                                             2-Me-4-Cl--Ph                                                                           131-132                                     551.sup.f                                                                         C--Me N(Et).sub.2      2,3-Me.sub.2 -4-OMe--Ph                                                                 oil                                         552.sup.g                                                                         C--Me N(CH.sub.2 CH.sub.2 OMe)CH.sub.2 CH.sub.2 OH                                                    2,4-Cl.sub.2 --Ph                                                                       oil                                         553.sup.h                                                                         C--Me N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,3-Me.sub.2 -4-OMe--Ph                                                                 oil                                         554.sup.i                                                                         C--Me NHCH(Et).sub.2   2,3-Me.sub.2 -4-OMePh                                                                   123-124                                     555.sup.j                                                                         C--Me N(CH.sub.2 -c-Pr)Pr                                                                             2-Me-4-Cl--Ph                                                                           oil                                         556.sup.k                                                                         C--Me N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2,3-Me.sub.2 -4-OMePh                                                                   158-160                                     557                                                                               C--Me N(c-Pr)Et        2-Cl-4-OMePh                                         558                                                                               C--Me N(c-Pr)Me        2-Cl-4-OMePh                                         559                                                                               C--Me N(c-Pr)Pr        2-Cl-4-OMePh                                         560                                                                               C--Me N(c-Pr)Bu        2-Cl-4-OMePh                                         561.sup.l                                                                         C--Me N(Et).sub.2      2-Cl-4-CN--Ph                                                                           115-117                                     562                                                                               C--Me N(c-Pr).sub.2    2-Cl-4-OMe                                                                              127-129                                     563.sup.m                                                                         C--Me NHCH(CH.sub.2 OH).sub.2                                                                         2,4-Cl.sub.2 --Ph                                                                       128-129                                     564                                                                               C--Me N(c-Pr)Et        2-Br-4,5-(MeO)2Ph                                    565                                                                               C--Me N(c-Pr)Me        2-Br-4,5-(MeO)2Ph                                    566                                                                               C--Me NH-c-Pr          2-Me-4-MeOPh                                                                            126-128                                     567                                                                               C--Me NHCH(Et)CH2OH    2-Me-4-MeOPh                                                                            60-62                                       568                                                                               C--Me NMe.sub.2        2-Br-4,5-(MeO)2Ph                                    569                                                                               C--Me NHCH(Et).sub.2   2-Me-4-MeOPh                                                                            103-105                                     570                                                                               C--Me N(c-Pr)Et        2-Me-4-MeOPh                                                                            173-174                                     571                                                                               C--Me NH-2-pentyl      2,4-Cl.sub.2 --Ph                                                                       118-120                                     572                                                                               C--Me NHCH(Et)CH2CN    2,4-Cl.sub.2 --Ph                                                                       141-142                                     573                                                                               C--Me NHCH(Pr)CH2OMe   2,4-Cl.sub.2 --Ph                                                                       87-88                                       574                                                                               C--Me NHCH(CH2-iPr)CH2OMe                                                                             2,4-Cl.sub.2 --Ph                                                                       amorphous                                   575                                                                               C--Me NH-2-butyl       2,4-Me.sub.2 --Ph                                                                       oil                                         576                                                                               C--Me NH-2-pentyl      2,4-Me.sub.2 --Ph                                                                       oil                                         577                                                                               C--Me NH-2-hexyl       2,4-Me.sub.2 --Ph                                                                       oil                                         578                                                                               C--Me NHCH(i-Pr)Me     2,4-Me.sub.2 --Ph                                                                       oil                                         579                                                                               C--Me NHCH(Me)CH2-iPr  2,4-Me.sub.2 --Ph                                                                       oil                                         580                                                                               C--Me NHCH(Me)-c-C6H11 2,4-Me.sub.2 --Ph                                                                       oil                                         581                                                                               C--Me NH-2-indanyl     2,4-Me.sub.2 --Ph                                                                       oil                                         582                                                                               C--Me NH-1-indanyl     2,4-Me.sub.2 --Ph                                                                       oil                                         583                                                                               C--Me NHCH(Me)Ph       2,4-Me.sub.2 --Ph                                                                       oil                                         584                                                                               C--Me NHCH(Me)CH.sub.2 -(4-ClPh)                                                                      2,4-Me.sub.2 --Ph                                                                       oil                                         585                                                                               C--Me NHCH(Me)CH.sub.2 COCH.sub.3                                                                     2,4-Me.sub.2 --Ph                                                                       oil                                         586                                                                               C--Me NHCH(Ph)CH.sub.2 Ph                                                                             2,4-Me.sub.2 --Ph                                                                       oil                                         587                                                                               C--Me NHCH(Me)(CH.sub.2)3NEt.sub.2                                                                    2,4-Me.sub.2 --Ph                                                                       oil                                         588                                                                               C--Me NH-(2-Ph-c-C.sub.3 H.sub.4)                                                                     2,4-Me.sub.2 --Ph                                                                       oil                                         589                                                                               C--Me NHCH(Et)CH.sub.2 CN                                                                             2,4-Me.sub.2 --Ph                                                                       119-120                                     590                                                                               C--Me NH-3-hexyl       2,4-Me.sub.2 --Ph                                                                       oil                                         591.sup.n                                                                         C--Me NEt.sub.2        2-MeO-4-ClPh                                                                            oil                                         592.sup.o                                                                         C--Me NHCH(Et).sub.2   2-MeO-4-ClPh                                                                            oil                                         593.sup.p                                                                         C--Me NHCH(Et)CH.sub.2 OMe                                                                            2-MeO-4-ClPh                                                                            oil                                         594                                                                               C--Me NMe.sub.2        2-MeO-4-ClPh                                                                            oil                                         595.sup.q                                                                         C--Me NHCH(Et).sub.2   2-OMe-4-MePh                                                                            oil                                         596.sup.r                                                                         C--Me NEt.sub.2        2-OMe-4-MePh                                                                            oil                                         597.sup.s                                                                         C-c-Pr                                                                               NHCH(CH.sub.2 OMe).sub.2                                                                        2,4-Cl.sub.2 --Ph                                                                       oil                                         598                                                                               C--Me N(c-Pr)Et        2,4-Me.sub.2 --Ph                                    599                                                                               C--Me N(c-Pr)Et        2,4-Cl.sub.2 --Ph                                    600                                                                               C--Me N(c-Pr)Et        2,4,6-Me.sub.3 --Ph                                  601                                                                               C--Me N(c-Pr)Et        2-Me-4-Cl--Ph                                        602                                                                               C--Me N(c-Pr)Et        2-Cl-4-Me--Ph                                        603                                                                               C--Me NHCH(c-Pr).sub.2 2,4-Cl.sub.2 --Ph                                    604                                                                               C--Me NHCH(c-Pr).sub.2 2,4-Me.sub.2 --Ph                                    605                                                                               C--Me NHCH(c-Pr).sub.2 2-Me-4-Cl--Ph                                        606                                                                               C--Me NHCH(c-Pr).sub.2 2-Cl-4-Me--Ph                                        607                                                                               C--Me NHCH(c-Pr).sub.2 2-Me-4-OMe--Ph                                       608                                                                               C--Me NHCH(c-Pr).sub.2 2-Cl-4-OMe--Ph                                       609                                                                               C--Me NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-5-F--OMePh                                      610                                                                               C--Me NEt.sub.2        2-Cl-5-F--OMePh                                      611                                                                               C--Me N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-Cl-5-F--OMePh                                      612                                                                               C--Me NHCH(Et).sub.2   2-Cl-5-F--OMePh                                      613                                                                               C--Me N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-5-F--OMePh                                      614                                                                               C--Me NEt.sub.2        2,6-Me.sub.2 -pyrid-3-yl                             615                                                                               C--Me N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2,6-Me.sub.2 -pyrid-3-yl                             616                                                                               C--Me NHCH(Et).sub.2   2,6-Me.sub.2 -pyrid-3-yl                             617                                                                               C--Me N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2, 6-Me.sub.2 -pyrid-3-yl                            618                                                                               C--OH NHCH(CH.sub.2 OMe).sub.2                                                                        2,4-Me.sub.2 --Ph                                    619                                                                               C--OH NEt.sub.2        2,4-Me.sub.2 --Ph                                    620                                                                               C--OH N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2,4-Me.sub.2 --Ph                                    621                                                                               C--OH NHCH(Et).sub.2   2,4-Me.sub.2 --Ph                                    623                                                                               C--OH N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4-Me.sub.2 --Ph                                    624                                                                               C--NEt.sub.2                                                                         NHCH(CH.sub.2 OMe).sub.2                                                                        2,4-Me.sub.2 --Ph                                    625                                                                               C--NEt.sub.2                                                                         NEt.sub.2        2,4-Me.sub.2 --Ph                                    626                                                                               C--NEt.sub.2                                                                         N(C--Pr)CH.sub.2 CH.sub.2 CN                                                                    2,4-Me.sub.2 --Ph                                    627                                                                               C--NEt.sub.2                                                                         NHCH(Et).sub.2   2,4-Me.sub.2 --Ph                                    628                                                                               C--NEt.sub.2                                                                         N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4-Me.sub.2 --Ph                                    629                                                                               C--Me NHCH(Et).sub.2   2-Me-4-CN--Ph                                        630                                                                               C--Me N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Me-4-CN--Ph                                        __________________________________________________________________________      Notes for Table 3:                                                             .sup.a CIHRMS: Calcd: 367.2610, Found: 367.2607(M+H);                          .sup.b CIHRMS: Calcd: 384.2400, Found: 384.2393(M+H);                          .sup.c CIHRMS: Calcd: 404.1853, Found: 404.1844(M+H);                          .sup.d CIHRMS: Calcd: 381.1594, Found: 381.1596(M+H);                          Analysis: Calcd: C: 63.07, H, 5.57, N, 22.07, Cl, 9.32; Found: C: 63.40,       H, 5.55, N, 21.96, Cl: 9.15                                                    .sup.e CIHRMS: Calcd: 369.1594, Found: 369.1576(M+H);                          .sup.f CIHRMS: Calcd: 354.2216, Found: 354.2211(M+H);                          .sup.g CIHRMS: Calcd: 410.1072, Found: 410.1075(M+H);                          .sup.h CIHRMS: Calcd: 414.2427, Found: 414.2427(M+H);                          .sup.i CIHRMS: Calcd: 368.2372, Found: 368.2372(M+H);                          .sup.j CIHRMS: Calcd: 384.1955, Found: 384.1947(M+H);                          .sup.k CIHRMS: Calcd: 391.2168, Found: 391.2160(M+H);                          .sup.l CIHRMS: Calcd: 335.1984, Found: 335.1961(M+H);                          .sup.m CIHRMS: Calcd: 382.0759, Found: 382.0765(M+H);                          .sup.n NH.sub.3 -CI MS: Calcd: 360, Found: 360(M+H)+-                          .sup.o NH.sub.3 -CI MS: Calcd: 374, Found: 374(M+H)+;                          NMR(CDCl.sub.3, 300 MHz): δ 7.29(d, J=8.4Hz, 1H), 7.04(dd, J=1.8,        8Hz, 1H), 6.96(d, J=1.8Hz, 1H), 6.15(d, J=10, 1H), 4.19(m, 1H), 3.81(s,        3H), 2.47(s, 3H), 2.32(s, 3H), 1.65 (m, 4H), 0.99(t, J=7.32Hz, 6H)             .sup.p NH.sub.3 -CI MS: Calcd: 390, Found: 390(M+H)+;                          NMR(CDCl.sub.3, 300 MHz): δ 7.28(d, J=8Hz, 1H), 7.03(d, J=8Hz, 1H),      6.96(s, 1H), 6.52(d, J=9Hz, 1H), 4.36(m, 1H), 3.8 (s, 3H), 3.55(m, 2H),        3.39(s, 3H), 2.47(s, 3H), 2.32(s, 3H), 1.76(m, 2H), 1.01(t, J=7.32Hz, 3H)      .sup.q CIHRMS: Calcd: 354.2294, Found: 354.2279(M+H)+-                         .sup.r CIHRMS: Calcd: 340.2137, Found: 340.2138(M+H)+-                         .sup.s CIHRMS: Calcd: 436.1307, Found: 436.1296(M+H)+-                   

The examples delineated in TABLE 4 may be prepared by the methods outlined in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example, EtOAc is ethyl acetate.

                  TABLE 4                                                          ______________________________________                                          ##STR40##                                                                     Ex.  Z        R.sub.3      Ar         mp (° C.)                         ______________________________________                                         631  C--Me    NHCH(Et).sub.2                                                                              2-Br-4,5-(MeO).sub.2 Ph                                                                   160-161                                  632  C--Me    NHCH(Et).sub.2                                                                              2-Br-4-MeOPh                                                                              110-111                                  633  C--Me    N(CH.sub.2 CH.sub.2 OMe).sub.2                                                              2-Br-4-MeOPh                                                                              74-76                                    634  C--Me    NHCH(CH.sub.2 OMe).sub.2                                                                    2-Br-4-MeOPh                                                                              128-130                                  635  C--Me    N(Et).sub.2  2-Me-4-ClPh                                                                               113-114                                  636  C--Me    N(c-Pr)Et    2,4-Cl.sub.2 Ph                                     637  C--Me    N(c-Pr)Et    2,4-Me.sub.2 Ph                                     638  C--Me    N(c-Pr)Et    2,4,6-Me.sub.3 Ph                                   639  C--Me    N(c-Pr)Et    2-Me-4-MeOPh                                        640  C--Me    N(c-Pr)Et    2-Cl-4-MeOPh                                        641  C--Me    N(c-Pr)Et    2-Cl-4-MePh                                         642  C--Me    N(c-Pr)Et    2-Me-4-ClPh                                         643  C--Me    NHCH(c-Pr).sub.2                                                                            2,4-Cl.sub.2 --Ph                                   644  C--Me    NHCH(c-Pr).sub.2                                                                            2,4-Me.sub.2 --Ph                                   645  C--Me    NHCH(c-Pr).sub.2                                                                            2-Me-4-Cl--Ph                                       646  C--Me    NHCH(c-Pr).sub.2                                                                            2-Cl-4-Me--Ph                                       647  C--Me    NHCH(c-Pr).sub.2                                                                            2-Me-4-OMe--Ph                                      648  C--Me    NHCH(c-Pr).sub.2                                                                            2-Cl-4-OMe--Ph                                      649  C--Me    NHCH(CH.sub.2 OMe).sub.2                                                                    2-Cl-5-F--OMePh                                     650  C--Me    NEt.sub.2    2-Cl-5-F-OMePh                                      651  C--Me    N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                 2-Cl-5-F--OMePh                                     652  C--Me    NHCH(Et).sub.2                                                                              2-Cl-5-F-OMePh                                      653  C--Me    N(CH.sub.2 CH.sub.2 OMe).sub.2                                                              2-Cl-5-F--OMePh                                     654  C--Me    NEt.sub.2    2,6-Me.sub.2 -pyrid-3-yl                            655  C--Me    N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                 2,6-Me.sub.2 -pyrid-3-yl                            656  C--Me    NHCH(Et).sub.2                                                                              2,6-Me.sub.2 -pyrid-3-yl                            657  C--Me    N(CH.sub.2 CH.sub.2 OMe).sub.2                                                              2,6-Me.sub.2 -pyrid-3-yl                            658  C--OH    NHCH(CH.sub.2 OMe).sub.2                                                                    2,4-Me.sub.2 --Ph                                   659  C--OH    NEt.sub.2    2,4-Me.sub.2 --Ph                                   660  C--OH    N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                 2,4-Me.sub.2 --Ph                                   661  C--OH    NHCH(Et).sub.2                                                                              2,4-Me.sub.2 --Ph                                   662  C--OH    N(CH.sub.2 CH.sub.2 OMe).sub.2                                                              2,4-Me.sub.2 --Ph                                   663  C--NEt.sub.2                                                                            NHCH(CH.sub.2 OMe).sub.2                                                                    2,4-Me.sub.2 --Ph                                   664  C--NEt.sub.2                                                                            NEt.sub.2    2,4-Me.sub.2 --Ph                                   665  C--NEt.sub.2                                                                            N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                 2,4-Me.sub.2 --Ph                                   666  C--NEt.sub.2                                                                            NHCH(Et).sub.2                                                                              2,4-Me.sub.2 --Ph                                   667  C--NEt.sub.2                                                                            N(CH.sub.2 CH.sub.2 OMe).sub.2                                                              2,4-Me.sub.2 --Ph                                   668  C--Me    NHCH(Et).sub.2                                                                              2-Me-4-CN--Ph                                       669  C--Me    N(CH.sub.2 CH.sub.2 OMe).sub.2                                                              2-Me-4-CN--Ph                                       ______________________________________                                    

The examples in Tables 5 or 6 may be prepared by the methods illustrated in Examples 1A, 1B, 2, 3, 6, 431, 432, 433, 434 or by appropriate combinations thereof. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

                  TABLE 5                                                          ______________________________________                                          ##STR41##                                                                     Ex.  R.sub.14                                                                              R.sub.3             Ar                                             ______________________________________                                         670  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,4-Cl.sub.2 --Ph                              671  Me     NHCHPr.sub.2        2,4-Cl.sub.2 --Ph                              672  Me     NEtBu               2,4-Cl.sub.2 --Ph                              673  Me     NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                                   2,4-Cl.sub.2 --Ph                              674  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,4-Cl.sub.2 --Ph                              675  Me     NH-3-heptyl         2,4-Cl.sub.2 --Ph                              676  Me     NHCH(Et)CH.sub.2 OMe                                                                               2,4-Cl.sub.2 --Ph                              677  Me     NEt.sub.2           2,4-Cl.sub.2 --Ph                              678  Me     NHCH(CH.sub.2 OEt).sub.2                                                                           2,4-Cl.sub.2 --Ph                              679  Me     NH-3-pentyl         2,4-Cl.sub.2 --Ph                              680  Me     NMePh               2,4-Cl.sub.2 --Ph                              681  Me     NPr.sub.2           2,4-Cl.sub.2 --Ph                              682  Me     NH-3-hexyl          2,4-Cl.sub.2 --Ph                              683  Me     morpholino          2,4-Cl.sub.2 --Ph                              684  Me     N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                                2,4-Cl.sub.2 --Ph                              685  Me     NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                      2,4-Cl.sub.2 --Ph                              686  Me     NH-4-tetrahydropyranyl                                                                             2,4-Cl.sub.2 --Ph                              687  Me     NH-cyclopentyl      2,4-Cl.sub.2 --Ph                              688  Me     OEt                 2,4-Cl.sub.2 --Ph                              689  Me     OCH(Et)CH.sub.2 OMe 2,4-Cl.sub.2 --Ph                              690  Me     OCH.sub.2 Ph        2,4-Cl.sub.2 --Ph                              691  Me     O-3-pentyl          2,4-Cl.sub.2 --Ph                              692  Me     SEt                 2,4-Cl.sub.2 --Ph                              693  Me     S(O)Et              2,4-Cl.sub.2 --Ph                              694  Me     SO.sub.2 Et         2,4-Cl.sub.2 --Ph                              695  Me     Ph                  2,4-Cl.sub.2 --Ph                              696  Me     2-CF.sub.3 --Ph     2,4-Cl.sub.2 --Ph                              697  Me     2-Ph--Ph            2,4-Cl.sub.2 --Ph                              698  Me     3-pentyl            2,4-Cl.sub.2 --Ph                              699  Me     cyclobutyl          2,4-Cl.sub.2 --Ph                              700  Me     3-pyridyl           2,4-Cl.sub.2 --Ph                              701  Me     CH(Et)CH.sub.2 CONMe.sub.2                                                                         2,4-Cl.sub.2 --Ph                              702  Me     CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                                  2,4-Cl.sub.2 --Ph                              703  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,4,6-Me.sub.3 --Ph                            704  Me     NHCHPr.sub.2        2,4,6-Me.sub.3 --Ph                            705  Me     NEtBu               2,4,6-Me.sub.3 --Ph                            706  Me     NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                                   2,4,6-Me.sub.3 --Ph                            707  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,4,6-Me.sub.3 --Ph                            708  Me     NH-3-heptyl         2,4,6-Me.sub.3 --Ph                            709  Me     NHCH(Et)CH.sub.2 OMe                                                                               2,4,6-Me.sub.3 --Ph                            710  Me     NEt.sub.2           2,4,6-Me.sub.3 --Ph                            711  Me     NHCH(CH.sub.2 OEt).sub.2                                                                           2,4,6-Me.sub.3 --Ph                            712  Me     NH-3-pentyl         2,4,6-Me.sub.3 --Ph                            713  Me     NMePh               2,4,6-Me.sub.3 --Ph                            714  Me     NPr.sub.2           2,4,6-Me.sub.3 --Ph                            715  Me     NH-3-hexyl          2,4,6-Me.sub.3 --Ph                            716  Me     morpholino          2,4,6-Me.sub.3 --Ph                            717  Me     N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                                2,4,6-Me.sub.3 --Ph                            718  Me     NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                      2,4,6-Me.sub.3 --Ph                            719  Me     NH-4-tetrahydropyranyl                                                                             2,4,6-Me.sub.3 --Ph                            720  Me     NH-cyclopentyl      2,4,6-Me.sub.3 --Ph                            721  Me     OEt                 2,4,6-Me.sub.3 --Ph                            722  Me     OCH(Et)CH.sub.2 OMe 2,4,6-Me.sub.3 --Ph                            723  Me     OCH.sub.2 Ph        2,4,6-Me.sub.3 --Ph                            724  Me     O-3-pentyl          2,4,6-Me.sub.3 --Ph                            725  Me     SEt                 2,4,6-Me.sub.3 --Ph                            726  Me     S(O)Et              2,4,6-Me.sub.3 --Ph                            727  Me     SO.sub.2 Et         2,4,6-Me.sub.3 --Ph                            728  Me     CH(CO.sub.2 Et).sub.2                                                                              2,4,6-Me.sub.3 --Ph                            729  Me     C(Et)(CO.sub.2 Et).sub.2                                                                           2,4,6-Me.sub.3 --Ph                            730  Me     CH(Et)CH.sub.2 OH   2,4,6-Me.sub.3 --Ph                            731  Me     CH(Et)CH.sub.2 OMe  2,4,6-Me.sub.3 --Ph                            732  Me     CONMe.sub.2         2,4,6-Me.sub.3 --Ph                            733  Me     COCH.sub.3          2,4,6-Me.sub.3 --Ph                            734  Me     CH(OH)CH.sub.3      2,4,6-Me.sub.3 --Ph                            735  Me     C(OH)Ph-3-pyridyl   2,4,6-Me.sub.3 --Ph                            736  Me     Ph                  2,4,6-Me.sub.3 --Ph                            737  Me     2-Ph--Ph            2,4,6-Me.sub.3 --Ph                            738  Me     3-pentyl            2,4,6-Me.sub.3 --Ph                            739  Me     cyclobutyl          2,4,6-Me.sub.3 --Ph                            740  Me     3-pyridyl           2,4,6-Me.sub.3 --Ph                            741  Me     CH(Et)CH.sub.2 CONMe.sub.2                                                                         2,4,6-Me.sub.3 --Ph                            742  Me     CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                                  2,4,6-Me.sub.3 --Ph                            743  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,4-Me.sub.2 --Ph                              744  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,4-Me.sub.2 --Ph                              745  Me     NHCH(Et)CH.sub.2 OMe                                                                               2,4-Me.sub.2 --Ph                              746  Me     NH-3-pentyl         2,4-Me.sub.2 --Ph                              747  Me     NEt.sub.2           2,4-Me.sub.2 --Ph                              748  Me     N(CH.sub.2 CN).sub.2                                                                               2,4-Me.sub.2 --Ph                              749  Me     NHCH(Me)CH.sub.2 OMe                                                                               2,4-Me.sub.2 --Ph                              750  Me     OCH(Et)CH.sub.2 OMe 2,4-Me.sub.2 --Ph                              751  Me     NPr-c-C.sub.3 H.sub.5                                                                              2,4-Me.sub.2 --Ph                              752  Me     NHCH(Me)CH.sub.2 NMe.sub.2                                                                         2,4-Me.sub.2 --Ph                              753  Me     N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                           2,4-Me.sub.2 --Ph                              754  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2,4-Me.sub.2 --Ph                              755  Me     N(Bu)CH.sub.2 CH.sub.2 CN                                                                          2,4-Me.sub.2 --Ph                              756  Me     NHCHPr.sub.2        2,4-Me.sub.2 --Ph                              757  Me     NEtBu               2,4-Me.sub.2 --Ph                              758  Me     NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                                   2,4-Me.sub.2 --Ph                              759  Me     NH-3-heptyl         2,4-Me.sub.2 --Ph                              760  Me     NEt.sub.2           2,4-Me.sub.2 --Ph                              761  Me     NHCH(CH.sub.2 OEt).sub.2                                                                           2,4-Me.sub.2 --Ph                              762  Me     NH-3-pentyl         2,4-Me.sub.2 --Ph                              763  Me     NMePh               2,4-Me.sub.2 --Ph                              764  Me     NPr.sub.2           2,4-Me.sub.2 --Ph                              765  Me     NH-3-hexyl          2,4-Me.sub.2 --Ph                              766  Me     morpholino          2,4-Me.sub.2 --Ph                              767  Me     N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                                2,4-Me.sub.2 --Ph                              768  Me     NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                      2,4-Me.sub.2 --Ph                              769  Me     NH-4-tetrahydropyranyl                                                                             2,4-Me.sub.2 --Ph                              770  Me     NH-cyclopentyl      2,4-Me.sub.2 --Ph                              771  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Me-4-MeO--Ph                                 772  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Me-4-MeO--Ph                                 773  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Me-4-MeO--Ph                                 774  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Me-4-MeO--Ph                                 775  Me     OCH(Et)CH.sub.2 OMe 2-Me-4-MeO--Ph                                 776  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4-MeO--Ph                                 777  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4-MeO--Ph                                 778  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Br-4-MeO--Ph                                 779  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Br-4-MeO--Ph                                 780  Me     OCH(Et)CH.sub.2 OMe 2-Br-4-MeO--Ph                                 781  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Me-4-NMe.sub.2 --Ph                          782  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Me-4-NMe.sub.2 --Ph                          783  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Me-4-NMe.sub.2 --Ph                          784  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Me-4-NMe.sub.2 --Ph                          785  Me     OCH(Et)CH.sub.2 OMe 2-Me-4-NMe.sub.2 --Ph                          786  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4-NMe.sub.2 --Ph                          787  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4-NMe.sub.2 --Ph                          788  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Br-4-NMe.sub.2 --Ph                          789  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Br-4-NMe.sub.2 --Ph                          790  Me     OCH(Et)CH.sub.2 OMe 2-Br-4-NMe.sub.2 --Ph                          791  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4-i-Pr--Ph                                792  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4-i-Pr--Ph                                793  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Br-4-i-Pr--Ph                                794  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Br-4-i-Pr--Ph                                795  Me     OCH(Et)CH.sub.2 OMe 2-Br-4-i-Pr--Ph                                796  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4-Me--Ph                                  797  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4-Me--Ph                                  798  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Br-4-Me--Ph                                  799  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Br-4-Me--Ph                                  800  Me     OCH(Et)CH.sub.2 OMe 2-Br-4-Me--Ph                                  801  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Me-4-Br--Ph                                  802  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Me-4-Br--Ph                                  803  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Me-4-Br--Ph                                  804  Me     N(Pr)CH.sub.2 CH.sub.2 CN                                                                          2-Me-4-Br--Ph                                  805  Me     OCH(Et)CH.sub.2 OMe 2-Me-4-Br--Ph                                  806  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Cl-4,6-Me.sub.2 --Ph                         807  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Cl-4,6-Me.sub.2 --Ph                         808  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           4-Br-2,6-(Me).sub.2 --Ph                       809  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     4-Br-2,6-(Me).sub.2 --Ph                       810  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           4-i-Pr-2-SMe--Ph                               811  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     4-i-Pr-2-SMe--Ph                               812  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4-CF.sub.3 --Ph                           813  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4-CF.sub.3 --Ph                           814  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4,6-(MeO).sub.2 --Ph                      815  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4,6-(MeO).sub.2 --Ph                      816  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Cl-4,6-(MeO).sub.2 --Ph                      817  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Cl-4,6-(MeO).sub.2 --Ph                      818  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,6-(Me).sub.2 -4-                                                             SMe--Ph                                        819  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,6-(Me).sub.2 -4-                                                             SMe--Ph                                        820  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           4-(COMe)-2-Br--Ph                              821  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     4-(COMe)-2-Br--Ph                              822  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,4,6-Me.sub.3 -pyrid-                                                         3-yl                                           823  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,4,6-Me.sub.3 -pyrid-                                                         3-yl                                           824  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,4-(Br).sub.2 --Ph                            825  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,4-(Br).sub.2 --Ph                            826  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           4-i-Pr-2-SMe--Ph                               827  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     4-i-Pr-2-SMe--Ph                               828  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           4-i-Pr-2-SO.sub.2 Me--Ph                       829  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     4-i-Pr-2-SO.sub.2 Me--Ph                       830  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,6-(Me).sub.2 -4-                                                             SMe--Ph                                        831  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,6-(Me).sub.2 -4-                                                             SMe--Ph                                        832  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,6-(Me)2-4-                                                                   SO.sub.2 Me--Ph                                833  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,6-(Me)2-4-                                                                   SO.sub.2 Me--Ph                                834  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-I-4-i-Pr--Ph                                 835  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-I-4-i-Pr--Ph                                 836  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4-N(Me).sub.2 -6-                                                         MeO--Ph                                        837  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4-N(Me).sub.2 -6                                                          MeO--Ph                                        838  Me     NEt.sub.2           2-Br-4-MeO--Ph                                 839  Me     NH-3-pentyl         2-Br-4-MeO--Ph                                 840  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-CN-4-Me--Ph                                  841  Me     N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                           2,4,6-Me.sub.3 --Ph                            842  Me     NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                            2-Me-4-Br--Ph                                  843  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2,5-Me.sub.2 -4-MeO--Ph                        844  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2,5-Me.sub.2 -4-MeO--Ph                        845  Me     NH-3-pentyl         2,5-Me.sub.2 -4-MeO--Ph                        846  Me     NEt.sub.2           2,5-Me.sub.2 -4-MeO--Ph                        847  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Cl-4-MePh                                    848  Me     NCH(Et)CH.sub.2 OMe 2-Cl-4-MePh                                    849  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Cl-4-MePh                                    850  Me     (S)--NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                       2-Cl-4-MePh                                    851  Me     N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                           2,5-Me.sub.2 -4-MeOPh                          852  Me     NEt.sub.2           2-Me-4-MeOPh                                   853  Me     OEt                 2-Me-4-MeOPh                                   854  Me     (S)--NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                       2-Me-4-MeOPh                                   855  Me     N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                           2-Me-4-MeOPh                                   856  Me     NHCH(CH.sub.2 CH.sub.2 OEt).sub.2                                                                  2-Me-4-MeOPh                                   857  Me     N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                           2,4-Cl.sub.2 --Ph                              858  Me     NEt.sub.2           2-Me-4-ClPh                                    859  Me     NH-3-pentyl         2-Me-4-ClPh                                    860  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Me-4-ClPh                                    861  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Me-4-ClPh                                    862  Me     NEt.sub.2           2-Me-4-ClPh                                    863  Me     NEt.sub.2           2-Cl-4-MePh                                    864  Me     NH-3-pentyl         2-Cl-4-MePh                                    865  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Cl-4-MeOPh                                   866  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Cl-4-MeOPh                                   867  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Cl-4-MeOPh                                   868  Me     N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                        2-Cl-4-MeOPh                                   869  Me     NEt.sub.2           2-Cl-4-MeOPh                                   870  Me     NH-3-pentyl         2-Cl-4-MeOPh                                   871  Me     NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                      2-Cl-4-MeOPh                                   872  Me     NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                      2-Cl-4-MeOPh                                   873  Me     NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                      2-Br-4-MeOPh                                   874  Me     NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                      2-Br-4-MeOPh                                   875  Me     NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                      2-Me-4-MeOPh                                   876  Me     NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                      2-Me-4-MeOPh                                   877  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Cl-4,5-(MeO).sub.2 Ph                        878  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Cl-4,5-(MeO).sub.2 Ph                        879  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Cl-4,5-(MeO).sub.2 Ph                        880  Me     N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                        2-Cl-4,5-(MeO).sub.2 Ph                        881  Me     NEt.sub.2           2-Cl-4,5-(MeO).sub.2 Ph                        882  Me     NH-3-pentyl         2-Cl-4,5-(MeO).sub.2 Ph                        883  Me     NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                      2-Cl-4,5-(MeO).sub.2 Ph                        884  Me     NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                      2-Cl-4,5-(MeO).sub.2 Ph                        885  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Br-4,5-(MeO).sub.2 Ph                        886  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Br-4,5-(MeO).sub.2 Ph                        887  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Br-4,5-(MeO).sub.2 Ph                        888  Me     N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                        2-Br-4,5-(MeO).sub.2 Ph                        889  Me     NEt.sub.2           2-Br-4,5-(MeO).sub.2 Ph                        890  Me     NH-3-pentyl         2-Br-4,5-(MeO).sub.2 Ph                        891  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Cl-4,6-(MeO).sub.2 Ph                        892  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Cl-4,6-(MeO).sub.2 Ph                        893  Me     NEt.sub.2           2-Cl-4,6-(MeO).sub.2 Ph                        894  Me     NH-3-pentyl         2-Cl-4,6-(MeO).sub.2 Ph                        895  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-Me-4,6-(MeO).sub.2 Ph                        896  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-Me-4,6-(MeO).sub.2 Ph                        897  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-Me-4,6-(MeO).sub.2 Ph                        898  Me     NEt.sub.2           2-Me-4,6-(MeO).sub.2 Ph                        899  Me     NH-3-pentyl         2-Me-4,6-(MeO).sub.2 Ph                        900  Me     NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                      2-Me-4-MeOPh                                   901  Me     NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                      2-Me-4-MeOPh                                   902  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-MeO-4-MePh                                   903  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-MeO-4-MePh                                   904  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-MeO-4-MePh                                   905  Me     N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                        2-MeO-4-MePh                                   906  Me     NEt.sub.2           2-MeO-4-MePh                                   907  Me     NH-3-pentyl         2-MeO-4-MePh                                   908  Me     NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                      2-MeO-4-MePh                                   909  Me     NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                      2-MeO-4-MePh                                   910  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-MeO-4-MePh                                   911  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-MeO-4-MePh                                   912  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-MeO-4-MePh                                   913  Me     N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                        2-MeO-4-MePh                                   914  Me     NEt.sub.2           2-MeO-4-MePh                                   915  Me     NH-3-pentyl         2-MeO-4-MePh                                   916  Me     NHCH(CH.sub.2 OMe).sub.2                                                                           2-MeO-4-ClPh                                   917  Me     N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                     2-MeO-4-ClPh                                   918  Me     NHCH(Et)CH.sub.2 OMe                                                                               2-MeO-4-ClPh                                   919  Me     NEt.sub.2           2-MeO-4-ClPh                                   920  Me     NH-3-pentyl         2-MeO-4-ClPh                                   ______________________________________                                    

                                      TABLE 6                                      __________________________________________________________________________      ##STR42##                                                                     Ex.                                                                               R.sub.14                                                                           R.sub.3          Ar                                                     __________________________________________________________________________      921                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,4-Cl.sub.2 --Ph                                       922                                                                              Me  NHCHPr.sub.2     2,4-Cl.sub.2 --Ph                                       923                                                                              Me  NEtBu            2,4-Cl.sub.2 --Ph                                       924                                                                              Me  NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                                2,4-Cl.sub.2 --Ph                                       925                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4-Cl.sub.2 --Ph                                       926                                                                              Me  NH-3-heptyl      2,4-Cl.sub.2 --Ph                                       927                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2,4-Cl.sub.2 --Ph                                       928                                                                              Me  NEt.sub.2        2,4-Cl.sub.2 --Ph                                       929                                                                              Me  NHCH(CH.sub.2 OEt).sub.2                                                                        2,4-Cl.sub.2 --Ph                                       930                                                                              Me  NH-3-pentyl      2,4-Cl.sub.2 --Ph                                       931                                                                              Me  NMePh            2,4-Cl.sub.2 --Ph                                       932                                                                              Me  NPr.sub.2        2,4-Cl.sub.2 --Ph                                       933                                                                              Me  NH-3-hexyl       2,4-Cl.sub.2 --Ph                                       934                                                                              Me  morpholino       2,4-Cl.sub.2 --Ph                                       935                                                                              Me  N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                             2,4-Cl.sub.2 --Ph                                       936                                                                              Me  NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                   2,4-Cl.sub.2 --Ph                                       937                                                                              Me  NH-4-tetrahydropyranyl                                                                          2,4-Cl.sub.2 --Ph                                       938                                                                              Me  NH-cyclopentyl   2,4-Cl.sub.2 --Ph                                       939                                                                              Me  OEt              2,4-Cl.sub.2 --Ph                                       940                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2,4-Cl.sub.2 --Ph                                       941                                                                              Me  OCH.sub.2 Ph     2,4-Cl.sub.2 --Ph                                       942                                                                              Me  O-3-pentyl       2,4-Cl.sub.2 --Ph                                       943                                                                              Me  SEt              2,4-Cl.sub.2 --Ph                                       944                                                                              Me  S(O)Et           2,4-Cl.sub.2 --Ph                                       945                                                                              Me  SO.sub.2 Et      2,4-Cl.sub.2 --Ph                                       946                                                                              Me  Ph               2,4-Cl.sub.2 --Ph                                       947                                                                              Me  2-CF.sub.3 --Ph  2,4-Cl.sub.2 --Ph                                       948                                                                              Me  2-Ph--Ph         2,4-Cl.sub.2 --Ph                                       949                                                                              Me  3-pentyl         2,4-Cl.sub.2 --Ph                                       950                                                                              Me  cyclobutyl       2,4-Cl.sub.2 --Ph                                       951                                                                              Me  3-pyridyl        2,4-Cl.sub.2 --Ph                                       952                                                                              Me  CH(Et)CH.sub.2 CONMe.sub.2                                                                      2,4-Cl.sub.2 --Ph                                       953                                                                              Me  CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                               2,4-Cl.sub.2 --Ph                                       954                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,4,6-Me.sub.3 --Ph                                     955                                                                              Me  NHCHPr.sub.2     2,4,6-Me.sub.3 --Ph                                     956                                                                              Me  NEtBu            2,4,6-Me.sub.3 --Ph                                     957                                                                              Me  NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                                2,4,6-Me.sub.3 --Ph                                     958                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4,6-Me.sub.3 --Ph                                     959                                                                              Me  NH-3-heptyl      2,4,6-Me.sub.3 --Ph                                     960                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2,4,6-Me.sub.3 --Ph                                     961                                                                              Me  NEt.sub.2        2,4,6-Me.sub.3 --Ph                                     962                                                                              Me  NHCH(CH.sub.2 OEt).sub.2                                                                        2,4,6-Me.sub.3 --Ph                                     963                                                                              Me  NH-3-pentyl      2,4,6-Me.sub.3 --Ph                                     964                                                                              Me  NMePh            2,4,6-Me.sub.3 --Ph                                     965                                                                              Me  NPr.sub.2        2,4,6-Me.sub.3 --Ph                                     966                                                                              Me  NH-3-hexyl       2,4,6-Me.sub.3 --Ph                                     967                                                                              Me  morpholino       2,4,6-Me.sub.3 --Ph                                     968                                                                              Me  N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                             2,4,6-Me.sub.3 --Ph                                     969                                                                              Me  NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                   2,4,6-Me.sub.3 --Ph                                     970                                                                              Me  NH-4-tetrahydropyranyl                                                                          2,4,6-Me.sub.3 --Ph                                     971                                                                              Me  NH-cyclopentyl   2,4,6-Me.sub.3 --Ph                                     972                                                                              Me  OEt              2,4,6-Me.sub.3 --Ph                                     973                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2,4,6-Me.sub.3 --Ph                                     974                                                                              Me  OCH.sub.2 Ph     2,4,6-Me.sub.3 --Ph                                     975                                                                              Me  O-3-pentyl       2,4,6-Me.sub.3 --Ph                                     976                                                                              Me  SEt              2,4,6-Me.sub.3 --Ph                                     977                                                                              Me  S(O)Et           2,4,6-Me.sub.3 --Ph                                     978                                                                              Me  SO.sub.2 Et      2,4,6-Me.sub.3 --Ph                                     979                                                                              Me  CH(CO.sub.2 Et).sub.2                                                                           2,4,6-Me.sub.3 --Ph                                     980                                                                              Me  C(Et)(CO.sub.2 Et).sub.2                                                                        2,4,6-Me.sub.3 --Ph                                     981                                                                              Me  CH(Et)CH.sub.2 OH                                                                               2,4,6-Me.sub.3 --Ph                                     982                                                                              Me  CH(Et)CH.sub.2 OMe                                                                              2,4,6-Me.sub.3 --Ph                                     983                                                                              Me  CONMe.sub.2      2,4,6-Me.sub.3 --Ph                                     984                                                                              Me  COCH.sub.3       2,4,6-Me.sub.3 --Ph                                     985                                                                              Me  CH(OH)CH.sub.3   2,4,6-Me.sub.3 --Ph                                     986                                                                              Me  C(OH)Ph-3-pyridyl                                                                               2,4,6-Me.sub.3 --Ph                                     987                                                                              Me  Ph               2,4,6-Me.sub.3 --Ph                                     988                                                                              Me  2-Ph--Ph         2,4,6-Me.sub.3 --Ph                                     989                                                                              Me  3-pentyl         2,4,6-Me.sub.3 --Ph                                     990                                                                              Me  cyclobutyl       2,4,6-Me.sub.3 --Ph                                     991                                                                              Me  3-pyridyl        2,4,6-Me.sub.3 --Ph                                     992                                                                              Me  CH(Et)CH.sub.2 CONMe.sub.2                                                                      2,4,6-Me.sub.3 --Ph                                     993                                                                              Me  CH(Et)CH.sub.2 CH.sub.2 NMe.sub.2                                                               2,4,6-Me.sub.3 --Ph                                     994                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,4-Me.sub.2 --Ph                                       995                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4-Me.sub.2 --Ph                                       996                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2,4-Me.sub.2 --Ph                                       997                                                                              Me  NH-3-pentyl      2,4-Me.sub.2 --Ph                                       998                                                                              Me  NEt.sub.2        2,4-Me.sub.2 --Ph                                       999                                                                              Me  N(CH.sub.2 CN).sub.2                                                                            2,4-Me.sub.2 --Ph                                      1000                                                                              Me  NHCH(Me)CH.sub.2 OMe                                                                            2,4-Me.sub.2 --Ph                                      1001                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2,4-Me.sub.2 --Ph                                      1002                                                                              Me  NPr-c-C.sub.3 H.sub.5                                                                           2,4-Me.sub.2 --Ph                                      1003                                                                              Me  NHCH(Me)CH.sub.2 NMe.sub.2                                                                      2,4-Me.sub.2 --Ph                                      1004                                                                              Me  N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                        2,4-Me.sub.2 --Ph                                      1005                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2,4-Me.sub.2 --Ph                                      1006                                                                              Me  N(Bu)CH.sub.2 CH.sub.2 CN                                                                       2,4-Me.sub.2 --Ph                                      1007                                                                              Me  NHCHPr.sub.2     2,4-Me.sub.2 --Ph                                      1008                                                                              Me  NEtBu            2,4-Me.sub.2 --Ph                                      1009                                                                              Me  NPr(CH.sub.2 -c-C.sub.3 H.sub.5)                                                                2,4-Me.sub.2 --Ph                                      1010                                                                              Me  NH-3-heptyl      2,4-Me.sub.2 --Ph                                      1011                                                                              Me  NEt.sub.2        2,4-Me.sub.2 --Ph                                      1012                                                                              Me  NHCH(CH.sub.2 OEt).sub.2                                                                        2,4-Me.sub.2 --Ph                                      1013                                                                              Me  NH-3-pentyl      2,A-Me.sub.2 --Ph                                      1014                                                                              Me  NMePh            2,4-Me.sub.2 --Ph                                      1015                                                                              Me  NPr.sub.2        2,4-Me.sub.2 --Ph                                      1016                                                                              Me  NH-3-hexyl       2,4-Me.sub.2 --Ph                                      1017                                                                              Me  morpholino       2,4-Me.sub.2 --Ph                                      1018                                                                              Me  N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 OMe                                                             2,4-Me.sub.2 --Ph                                      1019                                                                              Me  NHCH(CH.sub.2 Ph)CH.sub.2 OMe                                                                   2,4-Me.sub.2 --Ph                                      1020                                                                              Me  NH-4-tetrahydropyranyl                                                                          2,4-Me.sub.2 --Ph                                      1021                                                                              Me  NH-cyclopentyl   2,4-Me.sub.2 --Ph                                      1022                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Me-4-MeO--Ph                                         1023                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Me-4-MeO--Ph                                         1024                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Me-4-MeO--Ph                                         1025                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Me-4-MeO--Ph                                         1026                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Me-4-MeO--Ph                                         1027                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-MeO--Ph                                         1028                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4-MeO--Ph                                         1029                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Br-4-MeO--Ph                                         1030                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Br-4-MeO--Ph                                         1031                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Br-4-MeO--Ph                                         1032                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Me-4-NMe.sub.2 --Ph                                  1033                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Me-4-NMe.sub.2 --Ph                                  1034                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Me-4-NMe.sub.2 --Ph                                  1035                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Me-4-NMe.sub.2 --Ph                                  1036                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Me-4-NMe.sub.2 --Ph                                  1037                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-NMe.sub.2 --Ph                                  1038                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4-NMe.sub.2 --Ph                                  1039                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Br-4-NMe.sub.2 --Ph                                  1040                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Br-4-NMe.sub.2 --Ph                                  1041                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Br-4-NMe.sub.2 --Ph                                  1042                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-i-Pr-Ph                                         1043                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4-i-Pr--Ph                                        1044                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Br-4-i-Pr--Ph                                        1045                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Br-4-i-Pr--Ph                                        1046                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Br-4-i-Pr--Ph                                        1047                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-Me--Ph                                          1048                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4-Me--Ph                                          1049                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Br-4-Me--Ph                                          1050                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Br-4-Me--Ph                                          1051                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Br-4-Me--Ph                                          1052                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Me-4-Br--Ph                                          1053                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Me-4-Br--Ph                                          1054                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Me-4-Br--Ph                                          1055                                                                              Me  N(Pr)CH.sub.2 CH.sub.2 CN                                                                       2-Me-4-Br--Ph                                          1056                                                                              Me  OCH(Et)CH.sub.2 OMe                                                                             2-Me-4-Br--Ph                                          1057                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4,6-Me.sub.2 --Ph                                 1058                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-4,6-Me.sub.2 --Ph                                 1059                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        4-Br-2,6-(Me).sub.2 --Ph                               1060                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  4-Br-2,6-(Me).sub.2 --Ph                               1061                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        4-i-Pr-2-SMe--Ph                                       1062                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  4-i-Pr-2-SMe--Ph                                       1063                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-CF.sub.3 --Ph                                   1064                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4-CF.sub.3 --Ph                                   1065                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4,6-(MeO).sub.2 --Ph                              1066                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4,6-(MeO).sub.2 --Ph                              1067                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4,6-(MeO).sub.2 --Ph                              1068                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-4,6-(MeO).sub.2 --Ph                              1069                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,6-(Me).sub.2 -4-SMe--Ph                              1070                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,6-(Me).sub.2 -4-SMe--Ph                              1071                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        4-(COMe)-2-Br--Ph                                      1072                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  4-(COMe)-2-Br--Ph                                      1073                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,4,6-Me.sub.3 -pyrid-3-yl                             1074                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4,6-Me.sub.3 -pyrid-3-yl                             1075                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,4-(Br).sub.2 --Ph                                    1076                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,4-(Br).sub.2 --Ph                                    1077                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        4-i-Pr-2-SMe--Ph                                       1078                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  4-i-Pr-2-SMe--Ph                                       1079                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        4-i-Pr-2-SO.sub.2 Me--Ph                               1080                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  4-i-Pr-2-SO.sub.2 Me--Ph                               1081                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,6-(Me).sub.2 -4-SMe--Ph                              1082                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,6-(Me).sub.2 -4-SMe--Ph                              1083                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,6-(Me)2-4-SO.sub.2 Me--Ph                            1084                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,6-(Me)2-4-SO.sub.2 Me--Ph                            1085                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-I-4-i-Pr--Ph                                         1086                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-I-4-i-Pr--Ph                                         1087                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-N(Me).sub.2 -6-MeO--Ph                          1088                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4-N(Me).sub.2 -6-MeO--Ph                          1089                                                                              Me  NEt.sub.2        2-Br-4-MeO--Ph                                         1090                                                                              Me  NH-3-pentyl      2-Br-4-MeO--Ph                                         1091                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-CN-4-Me--Ph                                          1092                                                                              Me  N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                        2,4,6-Me.sub.3 --Ph                                    1093                                                                              Me  NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                         2-Me-4-Br--Ph                                          1094                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2,5-Me.sub.2 -4-MeO--Ph                                1095                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2,5-Me.sub.2 -4-MeO--Ph                                1096                                                                              Me  NH-3-pentyl      2,5-Me.sub.2 -4-MeO--Ph                                1097                                                                              Me  NEt.sub.2        2,5-Me.sub.2 -4-MeO--Ph                                1098                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4-MePh                                            1099                                                                              Me  NCH(Et)CH.sub.2 OMe                                                                             2-Cl-4-MePh                                            1100                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-4-MePh                                            1101                                                                              Me  (S)-NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                     2-Cl-4-MePh                                            1102                                                                              Me  N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                        2,5-Me.sub.2 -4-MeOPh                                  1103                                                                              Me  NEt.sub.2        2-Me-4-MeOPh                                           1104                                                                              Me  OEt              2-Me-4-MeOPh                                           1105                                                                              Me  (S)-NHCH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe                                                     2-Me-4-MeOPh                                           1106                                                                              Me  N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                        2-Me-4-MeOPh                                           1107                                                                              Me  NHCH(CH.sub.2 CH.sub.2 OEt).sub.2                                                               2-Me-4-MeOPh                                           1108                                                                              Me  N(c-C.sub.3 H.sub.5)CH.sub.2 CH.sub.2 CN                                                        2,4-Cl.sub.2 --Ph                                      1109                                                                              Me  NEt.sub.2        2-Me-4-ClPh                                            1110                                                                              Me  NH-3-pentyl      2-Me-4-ClPh                                            1111                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Me-4-ClPh                                            1112                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Me-4-ClPh                                            1113                                                                              Me  NEt.sub.2        2-Me-4-ClPh                                            1114                                                                              Me  NEt.sub.2        2-Cl-4-MePh                                            1115                                                                              Me  NH-3-pentyl      2-Cl-4-MePh                                            1116                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4-MeOPh                                           1117                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-4-MeOPh                                           1118                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Cl-4-MeOPh                                           1119                                                                              Me  N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-Cl-4-MeOPh                                           1120                                                                              Me  NEt.sub.2        2-Cl-4-MeOPh                                           1121                                                                              Me  NH-3-pentyl      2-Cl-4-MeOPh                                           1123                                                                              Me  NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                   2-Cl-4-MeOPh                                           1124                                                                              Me  NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                   2-Cl-4-MeOPh                                           1125                                                                              Me  NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                   2-Br-4-MeOPh                                           1126                                                                              Me  NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                   2-Br-4-MeOPh                                           1127                                                                              Me  NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                   2-Me-4-MeOPh                                           1128                                                                              Me  NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                   2-Me-4-MeOPh                                           1129                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4,5-(MeO).sub.2 Ph                                1130                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-4,5-(MeO).sub.2 Ph                                1131                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Cl-4,5-(MeO).sub.2 Ph                                1132                                                                              Me  N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-Cl-4,5-(MeO).sub.2 Ph                                1133                                                                              Me  NEt.sub.2        2-Cl-4,5-(MeO).sub.2 Ph                                1134                                                                              Me  NH-3-pentyl      2-Cl-4,5-(MeO).sub.2 Ph                                1135                                                                              Me  NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                   2-Cl-4,5-(MeO).sub.2 Ph                                1136                                                                              Me  NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                   2-Cl-4,5-(MeO).sub.2 Ph                                1137                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Br-4,5-(MeO).sub.2 Ph                                1138                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Br-4,5-(MeO).sub.2 Ph                                1139                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Br-4,5-(MeO).sub.2 Ph                                1140                                                                              Me  N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-Br-4,5-(MeO).sub.2 Ph                                1141                                                                              Me  NEt.sub.2        2-Br-4,5-(MeO).sub.2 Ph                                1142                                                                              Me  NH-3-pentyl      2-Br-4,5-(MeO).sub.2 Ph                                1143                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4,6-(MeO).sub.2 Ph                                1144                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Cl-4,6-(MeO).sub.2 Ph                                1145                                                                              Me  NEt.sub.2        2-Cl-4,6-(MeO).sub.2 Ph                                1146                                                                              Me  NH-3-pentyl      2-Cl-4,6-(MeO).sub.2 Ph                                1147                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-Me-4,6-(MeO).sub.2 Ph                                1148                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-Me-4,6-(MeO).sub.2 Ph                                1149                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-Me-4,6-(MeO).sub.2 Ph                                1150                                                                              Me  NEt.sub.2        2-Me-4,6-(MeO).sub.2 Ph                                1151                                                                              Me  NH-3-pentyl      2-Me-4,6-(MeO).sub.2 Ph                                1152                                                                              Me  NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                   2-Me-4-MeOPh                                           1153                                                                              Me  NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                   2-Me-4-MeOPh                                           1154                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-MeO-4-MePh                                           1155                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-MeO-4-MePh                                           1156                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-MeO-4-MePh                                           1157                                                                              Me  N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-MeO-4-MePh                                           1158                                                                              Me  NEt.sub.2        2-MeO-4-MePh                                           1159                                                                              Me  NH-3-pentyl      2-MeO-4-MePh                                           1160                                                                              Me  NHCH(Et)CH.sub.2 CH.sub.2 OMe                                                                   2-MeO-4-MePh                                           1161                                                                              Me  NHCH(Me)CH.sub.2 CH.sub.2 OMe                                                                   2-MeO-4-MePh                                           1162                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-MeO-4-MePh                                           1163                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-MeO-4-MePh                                           1164                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-MeO-4-MePh                                           1165                                                                              Me  N(c-Pr)CH.sub.2 CH.sub.2 CN                                                                     2-MeO-4-MePh                                           1166                                                                              Me  NEt.sub.2        2-MeO-4-MePh                                           1167                                                                              Me  NH-3-pentyl      2-MeO-4-MePh                                           1168                                                                              Me  NHCH(CH.sub.2 OMe).sub.2                                                                        2-MeO-4-ClPh                                           1169                                                                              Me  N(CH.sub.2 CH.sub.2 OMe).sub.2                                                                  2-MeO-4-ClPh                                           1170                                                                              Me  NHCH(Et)CH.sub.2 OMe                                                                            2-MeO-4-ClPh                                           1171                                                                              Me  NEt.sub.2        2-MeO-4-ClPh                                           1172                                                                              Me  NH-3-pentyl      2-MeO-4-ClPh                                           __________________________________________________________________________

Utility CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 `t` splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293ERNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000× g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000× g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 μl capacity. To each well is added 50 μl of test drug dilutions (final concentration of drugs range from 10-¹⁰ -10-⁵ M), 100 μl of ¹²⁵ I-ovine-CRF (¹²⁵ I-o-CRF) (final concentration 150 μM) and 150 μl of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of ¹²⁵ I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has a Ki value of less than about 10000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10⁻⁹ to 10^(-6m)) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/³² P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³ H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³² P]cAMP from [³² P]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). Compounds may be tested in any species of rodent or small mammal.

Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims. 

What is claimed is:
 1. A compound of Formula (50) ##STR43## and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, selected from the group consisting of:a compound of Formula (50) wherein R³ is --N(Et)(n--Bu), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; a compound of Formula (50) wherein R³ is --N(n--Pr) (CH₂ -cyclo-Pr), R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; a compound of Formula (50) wherein R³ is --NHCH(CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H. a compound of Formula (50) wherein R³ is --N(n--Pr)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; a compound of Formula (50) wherein R3 is --N(Et)₂, R^(4a) is Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H; a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H; a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H; a compound of Formula (50) wherein R³ is --N(Et)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; a compound of Formula (50) wherein R³ is --N(CH₂ CH₂ OMe)₂, R^(4a) is Cl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; and a compound of Formula (50) wherein R³ is N(CH₂ CH₂ OMe)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.
 2. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is selected from the group consisting of:4-(N-ethyl-N-butylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(N-(n-propyl)-N-(cyclopropyl)methylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(1,3-dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(dipropylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(diethylamino)-2,7-dimethyl-8-(2-bromo-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(diethylamino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(4-bromo-2-methylphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(diethylamino)-2,7-dimethyl-8-(2-chloro-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-chloro-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; and 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
 3. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is 4-(diethylamino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
 4. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound 4-(N-ethyl-N-butylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
 5. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is 4-(N-(n-propyl)-N-(cyclopropyl)methylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 1. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 2. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 3. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 4. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 5. 11. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
 12. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 11. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 12. 15. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 11. 16. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 12. 17. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 1. 18. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 2. 19. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 3. 20. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 4. 21. A method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of claim
 5. 